The PMM2 c.422G>A (p.R141H) pathogenic variant has previously been reported in the compound heterozygous state in congenital disorder of glycosylation type Ia, also called PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108).
ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.422G>A (p.Arg141His)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(60)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
60
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000303.3(PMM2):c.422G>A (p.Arg141His)
Variation ID: 7706 Accession: VCV000007706.124
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.2 16: 8811153 (GRCh38) [ NCBI UCSC ] 16: 8905010 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jan 13, 2025 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000303.3:c.422G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Arg141His missense NC_000016.10:g.8811153G>A NC_000016.9:g.8905010G>A NG_009209.1:g.18341G>A O15305:p.Arg141His - Protein change
- R141H
- Other names
- -
- Canonical SPDI
- NC_000016.10:8811152:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00359 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00338
Trans-Omics for Precision Medicine (TOPMed) 0.00345
1000 Genomes Project 0.00359
The Genome Aggregation Database (gnomAD), exomes 0.00407
Exome Aggregation Consortium (ExAC) 0.00660
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| PMM2 | - | - |
GRCh38 GRCh37 |
779 | 879 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (40) |
criteria provided, multiple submitters, no conflicts
|
May 6, 2024 | RCV000008145.79 | |
| Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
|
Jul 31, 2024 | RCV000078590.58 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 30, 2024 | RCV000624874.13 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001003990.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 6, 2020 | RCV000991177.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001003991.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001003989.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001257998.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 10, 2022 | RCV002255089.10 | |
|
PMM2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 26, 2024 | RCV003924813.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 22, 2019 | RCV004771801.1 | |
| click to load more click to collapse | ||||
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Feb 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511512.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Sep 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745326.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: research
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Congenital disorder of glycosylation, type Ia
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251487.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The PMM2 c.422G>A (p.R141H) pathogenic variant has previously been reported in the compound heterozygous state in congenital disorder of glycosylation type Ia, also called PMM2-congenital … (more)
The PMM2 c.422G>A (p.R141H) pathogenic variant has previously been reported in the compound heterozygous state in congenital disorder of glycosylation type Ia, also called PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108). (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194031.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000303.2(PMM2):c.422G>A(R141H) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Please note that in the homozygous state, R141H may be … (more)
NM_000303.2(PMM2):c.422G>A(R141H) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Please note that in the homozygous state, R141H may be associated with fetal demise. Sources cited for classification include the following: PMID 11058895, 9497260, 10854097, 21541725, 9781039, 26488408, 15844218, 10922383, 26014514, and 10386614. Classification of NM_000303.2(PMM2):c.422G>A(R141H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jan 04, 2021)
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criteria provided, single submitter
Method: research
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PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
inherited
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519164.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
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Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002766670.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ia (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (891 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated eukaryotic phosphomannomutase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg141Cys) variant has been classified as likely pathogenic by multiple clinical diagnostic laboratories (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been consistently classified as pathogenic by multiple clinical diagnostic laboratories and is the most common PMM2 pathogenic variant in Northern Europeans (ClinVar, GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Apr 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611238.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Jun 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018869.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000633725.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the PMM2 protein (p.Arg141His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the PMM2 protein (p.Arg141His). This variant is present in population databases (rs28936415, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). It is commonly reported in individuals of European ancestry (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). ClinVar contains an entry for this variant (Variation ID: 7706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711768.3
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Arg141His variant in PMM2 has been reported in several compound heterozygous individuals with congenital disorder of glycosylation type Ia and is one of the … (more)
The p.Arg141His variant in PMM2 has been reported in several compound heterozygous individuals with congenital disorder of glycosylation type Ia and is one of the most frequent pathogenic variants in patients with this disorder (Matthijs 1997 PMID: 9140401, Matthijs 1998 PMID: 9497260, de Lonlay 2001 PMID: 11134235). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7706) and has been identified in 0.7% (472/61238) of Finnish chromosomes and 0.6% (6521/1152934) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide evidence that this variant causes complete loss of enzyme activity (Vega 2011 PMID: 21541725, Andreotti 2015 PMID: 26488408). The p.Arg141His variant has never been observed in homozygosity, suggesting that the total absence of PMM2 activity is not compatible with life (Matthijs 1998 PMID: 9497260). Computational prediction tools and conservation analyses suggests that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation type Ia. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP4, PP3. (less)
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Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
PMM2-congenital disorder of glycosylation
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051939.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090188.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
|
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Pathogenic
(Jul 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321929.10
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a, but has only been identified in the compound heterozygous state and … (more)
One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a, but has only been identified in the compound heterozygous state and is predicted to be homozygous lethal (PMID: 11530212, 11517108); Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (PMID: 21541725); This variant is associated with the following publications: (PMID: 25192236, 20981092, 28373276, 28940310, 34670123, 34828263, 22975760, 10700701, 25333069, 21228398, 11530212, 9140401, 19357119, 11517108, 11589167, 27053713, 28139241, 23988505, 25108116, 16376131, 18629883, 19165618, 28425223, 28566178, 28820871, 30609409, 30487145, 30991241, 31474318, 31628766, 31981409, 31980526, 32595772, 32581362, 33580824, 11409861, 34277356, 33960646, 34426522, 32841164, 32064623, 31589614, 33163565, 32874916, 31736265, 33643843, 33204593, 33413482, 21541725, 32860008, 34055813, 33726816, 35279850, 34445196, 36099812, 36239000, 36773065, 35531120, 37541188, 35281664, 31902100, 37301908, 31391289, 26014514, 26488408) (less)
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Pathogenic
(Oct 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Focal segmental glomerulosclerosis
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Accession: SCV005382600.1
First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024 |
Comment:
This missense variant (c.422G>A, p.Arg141His) has been observed at very low frequency in population databases (gnomAD). It has been reported in the literature (PMID 24424129, … (more)
This missense variant (c.422G>A, p.Arg141His) has been observed at very low frequency in population databases (gnomAD). It has been reported in the literature (PMID 24424129, 9140401, 30061496). Variant prediction programs suggest a deleterious effect, and functional studies support this (PMID 21541725). This change was found in an affected patient. (less)
Clinical Features:
Focal segmental glomerulosclerosis (present)
Zygosity: Single Heterozygote
Age: 10-19 years
Sex: female
Tissue: blood
|
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Pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247655.27
First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024 |
Comment:
PMM2: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 18
|
|
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Pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001712854.5
First in ClinVar: Jun 15, 2021 Last updated: Dec 28, 2024 |
Comment:
PP3, PM3_very_strong, PS3
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Pathogenic
(Jul 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741460.6
First in ClinVar: Apr 15, 2018 Last updated: Jan 13, 2025 |
Comment:
The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide … (more)
The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.422G>A alteration was observed in 0.4% (891/224,376) of total alleles studied, with a frequency of 0.84% (177/21,196) in the European (Finnish) subpopulation. This missense alteration is the most frequent disease-causing PMM2 alteration and has been reported in several populations (Matthijs, 1997; Schollen, 2000; Vuillaumier-Barrot, 2000; Bohles, 2001; Quelhas, 2007). While the p.R141H alteration has been reported in compound heterozygosity with a second alteration in numerous patients with PMM2-related congenital disorder of glycosylation, no patients homozygous for this alteration have been reported, likely because it is a severe mutation and homozygosity would be lethal early in development (Matthijs, 1999). This amino acid position is highly conserved in available vertebrate species. The p.R141 amino acid is a crucial part of the distal phosphate binding site in the cap domain of α-PMM2, and loss of the positive charge at this location would impair substrate binding (Silvaggi, 2006). Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011). The p.R141H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Feb 18, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital disorder of glycosylation, type Ia
Affected status: unknown
Allele origin:
germline
|
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Accession: SCV000236521.2
First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015 |
|
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Pathogenic
(Jul 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences
Accession: SCV000693883.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal isoelectric focusing of serum transferrin (present) , Failure to thrive (present) , Visual impairment (present) , Esotropia (present) , Strabismus (present) , Hypotonia (present) … (more)
Abnormal isoelectric focusing of serum transferrin (present) , Failure to thrive (present) , Visual impairment (present) , Esotropia (present) , Strabismus (present) , Hypotonia (present) , Psychomotor retardation (present) , Microcephaly (present) , Synophrys (present) , Malformed ears (present) , Depressed nasal bridge (present) (less)
Zygosity: Compound Heterozygote
Family history: no
Age: 0-9 years
Sex: female
Geographic origin: Lebanon
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Pathogenic
(Oct 08, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743895.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
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Pathogenic
(Feb 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745882.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
|
|
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Pathogenic
(Apr 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000399674.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The PMM2 c.422G>A (p.Arg141His) missense variant is well-documented as the most common pathogenic variant found in patients with PMM2-associated congenital disorders of glycosylation (also known … (more)
The PMM2 c.422G>A (p.Arg141His) missense variant is well-documented as the most common pathogenic variant found in patients with PMM2-associated congenital disorders of glycosylation (also known as CDG-1a) (Sparks et al. 2015). The p.Arg141His variant was first described by Matthijs et al. (1997) in a group of 33 unrelated individuals with confirmed phosphomannomutase deficiency. In this study, the p.Arg141His variant was identified in a compound heterozygous state in ten affected individuals. A review by Matthijs et al. (2000) looking at over 249 patients from six different studies and 23 different countries concluded that the p.Arg141His variant accounts for 37 percent of all disease-associated alleles. This variant is typically observed in a compound heterozygous state in patients with severe phenotypes and has never been reported in a homozygous state (Sparks et al. 2015). When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999). The p.Arg141His variant is frequent in most populations and is reported at a frequency of 0.02756 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence the p.Arg141His variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Nov 11, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230903.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 46
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(Aug 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996184.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant is found in the compound heterozygous state in approximately 40% of individuals with Congenital disorder of glycosylation Type 1A of European ancestry (PMID: … (more)
This variant is found in the compound heterozygous state in approximately 40% of individuals with Congenital disorder of glycosylation Type 1A of European ancestry (PMID: 20301289). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.39% (891/224376). The c.422G>A (p.Arg141His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional characterization in multiple studies indicates that the p.Arg141His variant negatively impacts protein function including stability and enzymatic activity (PMID: 21541725, 26488408, 26014514). Based on the available evidence, the c.422G>A (p.Arg141His) variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Pediatric Metabolic Diseases, Hacettepe University
Accession: SCV000998567.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426499.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
|
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001435294.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Observation 1:
Zygosity: Compound Heterozygote
Family history: no
Sex: female
Secondary finding: no
Observation 2:
Zygosity: Compound Heterozygote
Family history: no
Sex: female
Secondary finding: no
Observation 3:
Number of individuals with the variant: 1
Family history: no
Sex: male
Secondary finding: no
|
|
|
Pathogenic
(Nov 18, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital disorder of glycosylation, type 1a
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448754.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Dystonia (present) , Spasticity (present) , Migraine (present) , Abnormality of the cerebral white matter (present) , Dysarthria (present) , Mutism (present) … (more)
Seizures (present) , Dystonia (present) , Spasticity (present) , Migraine (present) , Abnormality of the cerebral white matter (present) , Dysarthria (present) , Mutism (present) , Hypermetropia (present) , Abnormality of skin pigmentation (present) , Anemia (present) , Generalized muscle weakness (present) , Language impairment (present) (less)
Sex: female
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810578.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Nov 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696497.2
First in ClinVar: Mar 20, 2018 Last updated: Dec 25, 2021 |
Comment:
Variant summary: PMM2 c.422G>A (p.Arg141His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: PMM2 c.422G>A (p.Arg141His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 192974 control chromosomes. c.422G>A has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1997, Barone_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of PMM2 enzyme activity in one study (example, Vega_2011) and an oligomerization profile with a predominant aggregate fraction, less dimerization, nearly non-detectable enzymatic activities, and shorter degradation time in another study (example, Yuste-Checa_2015). Thus, variant severly affected both the folding as well as catalytic properties of the PMM2 protein . Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512215.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Geographic origin: Brazil
|
|
|
Pathogenic
(Jun 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital disorder of glycosylation type I
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002526393.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
The c.422G>A;p.(Arg141His)missense change one of most frequently variant associated with the phenotype described in the gene and ClinVar contains an entry for this variant (ClinVar … (more)
The c.422G>A;p.(Arg141His)missense change one of most frequently variant associated with the phenotype described in the gene and ClinVar contains an entry for this variant (ClinVar ID: 7706; PMID: 32860008; 32581362; 31474318; 28940310; 28373276; 25333069; 22975760; 21228398; 19357119; 11530212; 10700701; 9140401) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21541725, 26488408, 26014514) - PS3. The variant is present at low allele frequencies population databases (rs28936415– gnomAD 0.03660%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg141His) was detected in trans with a Pathogenic variant (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108; 19357119; 20301289; 21541725; 25355454) - PM3_very strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (c.421C>T (p.Arg141Cys) - PMID: 15844218) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(May 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557015.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
Comment:
The PMM2 c.422G>A variant is classified as PATHOGENIC (PM3, PP3, PS3, PS4) The PMM2 c.422G>A variant is a single nucleotide change in exon 5 of … (more)
The PMM2 c.422G>A variant is classified as PATHOGENIC (PM3, PP3, PS3, PS4) The PMM2 c.422G>A variant is a single nucleotide change in exon 5 of the PMM2 gene, which is predicted to change the amino acid arginine at position 141 in the protein to histidine. This is a recurrent variant and one of the most common PMM2 mutations (PS4). It is predicted to be homozygous lethal, so is only found in compound heterozygous state (PM3). Functional studies have demonstrated reduced enzyme stability and catalytic activity compared with wild type (PMID:21541725) (PS3). This variant is in dbSNP (rs28936415) and has been reported in population databases (gnomAD 891/224376 alleles, 0 homozygotes). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (ClinVar Variation ID: 22745). It is also classed as damaging for congenital disorder of glycosylation type 1a in HGMD (CM971228). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
|
|
|
Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841397.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.397%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.397%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007706). A different missense change at the same codon (p.Arg141Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550780). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Cerebral palsy (present) , Poor speech (present)
|
|
|
Pathogenic
(Oct 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920332.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
This variant has been reported in the literature as a compound heterozygote in several individuals with Congenital disorder of glycosylation type Ia (CDG-Ia) and segregating … (more)
This variant has been reported in the literature as a compound heterozygote in several individuals with Congenital disorder of glycosylation type Ia (CDG-Ia) and segregating with disease in affected family members. Of note, at least one publication notes that this variant is the most common pathogenic variant for this condition (Selected publications: Matthijs 1997 PMID:9140401, van Ommenn 2000 PMID:10700701, Briones 2001 PMID:11589167, Kjaergard 2001 PMID:11517108, Barone 2008 PMID:18629883, Vega 2011 PMID:21541725, Bastaki 2018 PMID:28940310). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.7% (82/10618) (https://gnomad.broadinstitute.org/variant/16-8811153-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID:7706). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies support that this variant will impact the protein by affecting folding and catalytic activity (Vega 2011 PMID:21541725, Yuste-Checa 2015 PMID:26014514). In summary, this variant is classified as pathogenic based on the data above. (less)
|
|
|
Pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: research
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920793.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Pathogenic
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004810049.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
|
Pathogenic
(Jan 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002072517.2
First in ClinVar: Feb 05, 2022 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS3,PS4,PM5_SUP,PP3
Sex: male
|
|
|
Pathogenic
(May 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005047051.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment:
A PMM2 c.422G>A (p.Arg141His) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with PMM2-related congenital disorders of glycosylation … (more)
A PMM2 c.422G>A (p.Arg141His) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with PMM2-related congenital disorders of glycosylation (Matthijs G et al., PMID: 9497260; Kjaergaard S et al., PMID: 11517108; Romano S et al., PMID: 19357119; Vega AI et al., PMID: 21541725; Barone R et al., PMID: 25355454; Matthijs G et al., PMID: 9140401; de Lonlay P et al., PMID: 11134235) and is one of the most frequent pathogenic variants in this gene. The PMM2 c.422G>A (p.Arg141His) variant has been reported in the ClinVar database as pathogenic by several submitters (ClinVar ID: 7706). The global population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.4%, which is consistent with the carrier frequency for this disorder based on the recent estimated incidence of disease (Pajusalu S et al., PMID: 34447415). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMM2 function. In support of this prediction, functional studies show that the p.Arg141His variant affects protein stability, indicating that this variant impacts protein function (Vega AI et al., PMID: 21541725; Yuste-Checa P et al., PMID: 26014514). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163402.4
First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197195.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(May 01, 2007)
|
no assertion criteria provided
Method: literature only
|
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028350.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015 |
Comment on evidence:
In a family in Sicily in which linkage studies indicated mapping of congenital disorder of glycosylation type I (CDG1A; 212065) to 16p13, Matthijs et al. … (more)
In a family in Sicily in which linkage studies indicated mapping of congenital disorder of glycosylation type I (CDG1A; 212065) to 16p13, Matthijs et al. (1997) found that affected individuals were compound heterozygous for a 425G-A transition (R141H) and a 647A-T transversion (N216I; 601785.0002) in the PMM2 gene. Among 18 unrelated Danish patients with CDG Ia, Kjaergaard et al. (1998) found that this and the F119L mutation (601785.0006) accounted for 88% of all mutations. Each was found in 16 of 36 PMM2 alleles. Matthijs et al. (1999) commented on the intriguing observation of the total lack of patients homozygous for the common R141H mutation. The residual activity of the in vitro expressed R141H recombinant protein is almost zero, supporting the inference that homozygosity for this mutation is lethal early in development. Patients homozygous for the relatively frequent F119L mutation have been found, and 1 patient homozygous for the D65Y mutation (601785.0005) has been identified. In these patients, the residual activity of the deficient enzyme was, in the words of Matthijs et al. (1999), 'relatively pronounced.' Schollen et al. (2000) determined the frequency of the R141H mutation in 2 normal populations: in neonates of Dutch origin, 1 in 79 were carriers, whereas in the Danish population, a carrier frequency of 1 in 60 was found. These figures were clearly in disequilibrium with the frequency of CDG Ia that had been estimated at 1 in 80,000 and 1 in 40,000 in these populations. Haplotype analysis of 43 patients with the R141H mutation of different geographic origins indicated that it is an old mutation in the Caucasian population. Based on the new data, the disease frequency was calculated at 1 in 20,000 in these populations. The authors concluded that the disease was probably underdiagnosed. Vuillaumier-Barrot et al. (2000) identified the R141H mutation in 9 (41%) of 22 chromosomes in French patients with CDG Ia. In a male infant diagnosed with CDG Ia, Bohles et al. (2001) showed a pro113-to-leu (P113L) mutation in compound heterozygosity with the arg141-to-his mutation. Quelhas et al. (2006) found that the R141H substitution was the most common mutation among 15 Portuguese patients with CDG1A, accounting for 7 of 26 mutations (26%). The second most common mutation was D65Y (601785.0005), which accounted for 6 of 26 mutations (23%). Haplotype analysis indicated a founder effect for the R141H substitution. (less)
|
|
|
Pathogenic
(Jan 06, 2020)
|
no assertion criteria provided
Method: curation
|
Congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142455.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000303.2:c.422G>A in the PMM2 gene has an allele frequency of 0.008 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg141His has reduced … (more)
NM_000303.2:c.422G>A in the PMM2 gene has an allele frequency of 0.008 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg141His has reduced protein stability and enzymatic activity in vitro (PMID: 26014514).It was detected in multiple individuals with autosomal recessive PMM2-CDG, compound heterozygous with c.710C>T (p.Thr237Met), c.484C>T (p.Arg162Trp), c.722G>C (p.Cys241Ser), c.677C>G (p.Thr226Ser) (PMID: 21541725).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Strong; PS3; PP4 (less)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Diabetes mellitus
Cerebellar ataxia Cerebellar hypoplasia Muscular dystrophy
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162015.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Cerebellar ataxia
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162016.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Cerebellar ataxia
Spasticity Cerebellar hypoplasia Cerebral atrophy Poor speech Cerebral palsy
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162017.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Number of individuals with the variant: 1
Sex: female
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957730.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733550.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
Pathogenic
(Feb 18, 2019)
|
no assertion criteria provided
Method: research
|
Carbohydrate-deficient glycoprotein syndrome type I
Affected status: yes
Allele origin:
germline
|
Dobyns Lab, Seattle Children's Research Institute
Accession: SCV000916324.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Number of individuals with the variant: 2
Sex: male
Ethnicity/Population group: Caucasian/Hispanic
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
unknown
|
Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001432387.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Cerebellar hypoplasia
Affected status: yes
Allele origin:
inherited
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001434811.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Congenital disorder of glycosylation type 1a
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001457174.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554206.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in … (more)
The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in ~40% of European CDG1a cases. This variant has only been found in the compound heterozygous state, suggesting that homozygosity for the p.A141H variant would be lethal (Matthijs_1998_PMID:9497260; Kjaergaard_1998_PMID:9781039). The variant was identified in dbSNP (ID: rs28936415) and ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and 15 other laboratories). The variant was identified in control databases in 891 of 224376 chromosomes at a frequency of 0.003971 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 177 of 21196 chromosomes (freq: 0.008351), Ashkenazi Jewish in 71 of 9376 chromosomes (freq: 0.007573), European (non-Finnish) in 511 of 94084 chromosomes (freq: 0.005431), Other in 27 of 6220 chromosomes (freq: 0.004341), Latino in 64 of 30676 chromosomes (freq: 0.002086), South Asian in 24 of 25492 chromosomes (freq: 0.000942), African in 15 of 20700 chromosomes (freq: 0.000725), and East Asian in 2 of 16632 chromosomes (freq: 0.00012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.R141 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800330.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925184.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Jun 21, 2021)
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no assertion criteria provided
Method: clinical testing
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PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070493.3
First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022 |
Comment:
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.422G>A, in exon 5 that results in an amino acid change, p.Arg141His. The p.Arg141His … (more)
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.422G>A, in exon 5 that results in an amino acid change, p.Arg141His. The p.Arg141His sequence change has been observed in 0.4% of individuals in the gnomAD database, in the heterozygous state, and is regarded as the most common pathogenic variant found in patients with PMM2-related congenital disorders of glycosylation (PMID: 20301289). The p.Arg141His change affects a highly conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Arg141His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in an estimated 40% of individuals with PMM2-related congenital disorders of glycosylation (CDG), in the compound heterozygous state with a second variant (PMID: 20301289, 21541725). Functional studies have also demonstrated that the p.Arg141His change reduces protein stability and enzymatic activity in vitro (PMID: 26014514) (less)
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Pathogenic
(Aug 26, 2024)
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no assertion criteria provided
Method: clinical testing
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PMM2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004739486.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PMM2 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been documented as causative for autosomal recessive congenital … (more)
The PMM2 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia (CDG-Ia), and is one of the most frequent pathogenic variants reported in the PMM2 gene (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Vega et al. 2011. PubMed ID: 21541725). The c.422G>A (p.Arg141His) variant is also reported as c.425G>A (p.Arg141His) in the literature. Functional in vitro studies on this variant have demonstrated that it severely impacts protein stability and activity (Vega et al. 2011. PubMed ID: 21541725). Additionally, a mouse model (compound heterozygous for variants corresponding to the human p.Arg141His and p.Phe119Leu variants) demonstrated prenatal death and significantly stunted growth in animals due to protein glycosylation deficiencies (Chan et al. 2016. PubMed ID: 27053713). Of note, the c.422G>A variant has been observed with a subpopulation (European) frequency up to ~0.8% in a large database of individuals with unknown phenotype. However, no homozygotes have been reported to date, and the c.422G>A (p.Arg141His) variant is suspected to be embryonically lethal when present in the homozygous state (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7706/). Taken together, we interpret this variant as pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749975.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 02-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 02-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Hypermetropia (present) , Abnormal lens morphology (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormal … (more)
Hypermetropia (present) , Abnormal lens morphology (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormal large intestine morphology (present) (less)
Indication for testing: Diagnostic
Age: 70-79 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-02-19
Testing laboratory interpretation: Pathogenic
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not provided
(-)
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no classification provided
Method: literature only
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PMM2-congenital disorder of glycosylation
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040585.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002818370.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant classified as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Cardiomyopathy (present) , Attention deficit hyperactivity disorder (present) , Rod-cone dystrophy (present)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Exome Sequencing
Testing laboratory: Genetic Services Laboratory,University of Chicago
Date variant was reported to submitter: 2018-06-29
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
NM_000303.2(PMM2):c.422G>A(R141H) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Please note that in the homozygous state, R141H may be associated with fetal demise. Sources cited for classification include the following: PMID 11058895, 9497260, 10854097, 21541725, 9781039, 26488408, 15844218, 10922383, 26014514, and 10386614. Classification of NM_000303.2(PMM2):c.422G>A(R141H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ia (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (891 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated eukaryotic phosphomannomutase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg141Cys) variant has been classified as likely pathogenic by multiple clinical diagnostic laboratories (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been consistently classified as pathogenic by multiple clinical diagnostic laboratories and is the most common PMM2 pathogenic variant in Northern Europeans (ClinVar, GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the PMM2 protein (p.Arg141His). This variant is present in population databases (rs28936415, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). It is commonly reported in individuals of European ancestry (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). ClinVar contains an entry for this variant (Variation ID: 7706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Arg141His variant in PMM2 has been reported in several compound heterozygous individuals with congenital disorder of glycosylation type Ia and is one of the most frequent pathogenic variants in patients with this disorder (Matthijs 1997 PMID: 9140401, Matthijs 1998 PMID: 9497260, de Lonlay 2001 PMID: 11134235). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7706) and has been identified in 0.7% (472/61238) of Finnish chromosomes and 0.6% (6521/1152934) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide evidence that this variant causes complete loss of enzyme activity (Vega 2011 PMID: 21541725, Andreotti 2015 PMID: 26488408). The p.Arg141His variant has never been observed in homozygosity, suggesting that the total absence of PMM2 activity is not compatible with life (Matthijs 1998 PMID: 9497260). Computational prediction tools and conservation analyses suggests that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation type Ia. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP4, PP3.
Comment:
One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a, but has only been identified in the compound heterozygous state and is predicted to be homozygous lethal (PMID: 11530212, 11517108); Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (PMID: 21541725); This variant is associated with the following publications: (PMID: 25192236, 20981092, 28373276, 28940310, 34670123, 34828263, 22975760, 10700701, 25333069, 21228398, 11530212, 9140401, 19357119, 11517108, 11589167, 27053713, 28139241, 23988505, 25108116, 16376131, 18629883, 19165618, 28425223, 28566178, 28820871, 30609409, 30487145, 30991241, 31474318, 31628766, 31981409, 31980526, 32595772, 32581362, 33580824, 11409861, 34277356, 33960646, 34426522, 32841164, 32064623, 31589614, 33163565, 32874916, 31736265, 33643843, 33204593, 33413482, 21541725, 32860008, 34055813, 33726816, 35279850, 34445196, 36099812, 36239000, 36773065, 35531120, 37541188, 35281664, 31902100, 37301908, 31391289, 26014514, 26488408)
Comment:
This missense variant (c.422G>A, p.Arg141His) has been observed at very low frequency in population databases (gnomAD). It has been reported in the literature (PMID 24424129, 9140401, 30061496). Variant prediction programs suggest a deleterious effect, and functional studies support this (PMID 21541725). This change was found in an affected patient.
Comment:
PMM2: PM3:Very Strong, PM2, PS3:Supporting
Comment:
PP3, PM3_very_strong, PS3
Comment:
The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.422G>A alteration was observed in 0.4% (891/224,376) of total alleles studied, with a frequency of 0.84% (177/21,196) in the European (Finnish) subpopulation. This missense alteration is the most frequent disease-causing PMM2 alteration and has been reported in several populations (Matthijs, 1997; Schollen, 2000; Vuillaumier-Barrot, 2000; Bohles, 2001; Quelhas, 2007). While the p.R141H alteration has been reported in compound heterozygosity with a second alteration in numerous patients with PMM2-related congenital disorder of glycosylation, no patients homozygous for this alteration have been reported, likely because it is a severe mutation and homozygosity would be lethal early in development (Matthijs, 1999). This amino acid position is highly conserved in available vertebrate species. The p.R141 amino acid is a crucial part of the distal phosphate binding site in the cap domain of α-PMM2, and loss of the positive charge at this location would impair substrate binding (Silvaggi, 2006). Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011). The p.R141H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The PMM2 c.422G>A (p.Arg141His) missense variant is well-documented as the most common pathogenic variant found in patients with PMM2-associated congenital disorders of glycosylation (also known as CDG-1a) (Sparks et al. 2015). The p.Arg141His variant was first described by Matthijs et al. (1997) in a group of 33 unrelated individuals with confirmed phosphomannomutase deficiency. In this study, the p.Arg141His variant was identified in a compound heterozygous state in ten affected individuals. A review by Matthijs et al. (2000) looking at over 249 patients from six different studies and 23 different countries concluded that the p.Arg141His variant accounts for 37 percent of all disease-associated alleles. This variant is typically observed in a compound heterozygous state in patients with severe phenotypes and has never been reported in a homozygous state (Sparks et al. 2015). When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999). The p.Arg141His variant is frequent in most populations and is reported at a frequency of 0.02756 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence the p.Arg141His variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant is found in the compound heterozygous state in approximately 40% of individuals with Congenital disorder of glycosylation Type 1A of European ancestry (PMID: 20301289). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.39% (891/224376). The c.422G>A (p.Arg141His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional characterization in multiple studies indicates that the p.Arg141His variant negatively impacts protein function including stability and enzymatic activity (PMID: 21541725, 26488408, 26014514). Based on the available evidence, the c.422G>A (p.Arg141His) variant is classified as Pathogenic.
Comment:
Variant summary: PMM2 c.422G>A (p.Arg141His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 192974 control chromosomes. c.422G>A has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1997, Barone_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of PMM2 enzyme activity in one study (example, Vega_2011) and an oligomerization profile with a predominant aggregate fraction, less dimerization, nearly non-detectable enzymatic activities, and shorter degradation time in another study (example, Yuste-Checa_2015). Thus, variant severly affected both the folding as well as catalytic properties of the PMM2 protein . Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Comment:
The c.422G>A;p.(Arg141His)missense change one of most frequently variant associated with the phenotype described in the gene and ClinVar contains an entry for this variant (ClinVar ID: 7706; PMID: 32860008; 32581362; 31474318; 28940310; 28373276; 25333069; 22975760; 21228398; 19357119; 11530212; 10700701; 9140401) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21541725, 26488408, 26014514) - PS3. The variant is present at low allele frequencies population databases (rs28936415– gnomAD 0.03660%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg141His) was detected in trans with a Pathogenic variant (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108; 19357119; 20301289; 21541725; 25355454) - PM3_very strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (c.421C>T (p.Arg141Cys) - PMID: 15844218) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Comment:
The PMM2 c.422G>A variant is classified as PATHOGENIC (PM3, PP3, PS3, PS4) The PMM2 c.422G>A variant is a single nucleotide change in exon 5 of the PMM2 gene, which is predicted to change the amino acid arginine at position 141 in the protein to histidine. This is a recurrent variant and one of the most common PMM2 mutations (PS4). It is predicted to be homozygous lethal, so is only found in compound heterozygous state (PM3). Functional studies have demonstrated reduced enzyme stability and catalytic activity compared with wild type (PMID:21541725) (PS3). This variant is in dbSNP (rs28936415) and has been reported in population databases (gnomAD 891/224376 alleles, 0 homozygotes). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (ClinVar Variation ID: 22745). It is also classed as damaging for congenital disorder of glycosylation type 1a in HGMD (CM971228). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.397%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007706). A different missense change at the same codon (p.Arg141Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550780). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been reported in the literature as a compound heterozygote in several individuals with Congenital disorder of glycosylation type Ia (CDG-Ia) and segregating with disease in affected family members. Of note, at least one publication notes that this variant is the most common pathogenic variant for this condition (Selected publications: Matthijs 1997 PMID:9140401, van Ommenn 2000 PMID:10700701, Briones 2001 PMID:11589167, Kjaergard 2001 PMID:11517108, Barone 2008 PMID:18629883, Vega 2011 PMID:21541725, Bastaki 2018 PMID:28940310). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.7% (82/10618) (https://gnomad.broadinstitute.org/variant/16-8811153-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID:7706). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies support that this variant will impact the protein by affecting folding and catalytic activity (Vega 2011 PMID:21541725, Yuste-Checa 2015 PMID:26014514). In summary, this variant is classified as pathogenic based on the data above.
Comment:
Criteria applied: PS3,PS4,PM5_SUP,PP3
Comment:
A PMM2 c.422G>A (p.Arg141His) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with PMM2-related congenital disorders of glycosylation (Matthijs G et al., PMID: 9497260; Kjaergaard S et al., PMID: 11517108; Romano S et al., PMID: 19357119; Vega AI et al., PMID: 21541725; Barone R et al., PMID: 25355454; Matthijs G et al., PMID: 9140401; de Lonlay P et al., PMID: 11134235) and is one of the most frequent pathogenic variants in this gene. The PMM2 c.422G>A (p.Arg141His) variant has been reported in the ClinVar database as pathogenic by several submitters (ClinVar ID: 7706). The global population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.4%, which is consistent with the carrier frequency for this disorder based on the recent estimated incidence of disease (Pajusalu S et al., PMID: 34447415). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMM2 function. In support of this prediction, functional studies show that the p.Arg141His variant affects protein stability, indicating that this variant impacts protein function (Vega AI et al., PMID: 21541725; Yuste-Checa P et al., PMID: 26014514). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Comment:
NM_000303.2:c.422G>A in the PMM2 gene has an allele frequency of 0.008 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg141His has reduced protein stability and enzymatic activity in vitro (PMID: 26014514).It was detected in multiple individuals with autosomal recessive PMM2-CDG, compound heterozygous with c.710C>T (p.Thr237Met), c.484C>T (p.Arg162Trp), c.722G>C (p.Cys241Ser), c.677C>G (p.Thr226Ser) (PMID: 21541725).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Strong; PS3; PP4
Comment:
The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in ~40% of European CDG1a cases. This variant has only been found in the compound heterozygous state, suggesting that homozygosity for the p.A141H variant would be lethal (Matthijs_1998_PMID:9497260; Kjaergaard_1998_PMID:9781039). The variant was identified in dbSNP (ID: rs28936415) and ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and 15 other laboratories). The variant was identified in control databases in 891 of 224376 chromosomes at a frequency of 0.003971 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 177 of 21196 chromosomes (freq: 0.008351), Ashkenazi Jewish in 71 of 9376 chromosomes (freq: 0.007573), European (non-Finnish) in 511 of 94084 chromosomes (freq: 0.005431), Other in 27 of 6220 chromosomes (freq: 0.004341), Latino in 64 of 30676 chromosomes (freq: 0.002086), South Asian in 24 of 25492 chromosomes (freq: 0.000942), African in 15 of 20700 chromosomes (freq: 0.000725), and East Asian in 2 of 16632 chromosomes (freq: 0.00012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.R141 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.422G>A, in exon 5 that results in an amino acid change, p.Arg141His. The p.Arg141His sequence change has been observed in 0.4% of individuals in the gnomAD database, in the heterozygous state, and is regarded as the most common pathogenic variant found in patients with PMM2-related congenital disorders of glycosylation (PMID: 20301289). The p.Arg141His change affects a highly conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Arg141His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in an estimated 40% of individuals with PMM2-related congenital disorders of glycosylation (CDG), in the compound heterozygous state with a second variant (PMID: 20301289, 21541725). Functional studies have also demonstrated that the p.Arg141His change reduces protein stability and enzymatic activity in vitro (PMID: 26014514)
Comment:
The PMM2 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia (CDG-Ia), and is one of the most frequent pathogenic variants reported in the PMM2 gene (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Vega et al. 2011. PubMed ID: 21541725). The c.422G>A (p.Arg141His) variant is also reported as c.425G>A (p.Arg141His) in the literature. Functional in vitro studies on this variant have demonstrated that it severely impacts protein stability and activity (Vega et al. 2011. PubMed ID: 21541725). Additionally, a mouse model (compound heterozygous for variants corresponding to the human p.Arg141His and p.Phe119Leu variants) demonstrated prenatal death and significantly stunted growth in animals due to protein glycosylation deficiencies (Chan et al. 2016. PubMed ID: 27053713). Of note, the c.422G>A variant has been observed with a subpopulation (European) frequency up to ~0.8% in a large database of individuals with unknown phenotype. However, no homozygotes have been reported to date, and the c.422G>A (p.Arg141His) variant is suspected to be embryonically lethal when present in the homozygous state (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7706/). Taken together, we interpret this variant as pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 02-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Comment:
Variant classified as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The PMM2 c.422G>A (p.R141H) pathogenic variant has previously been reported in the compound heterozygous state in congenital disorder of glycosylation type Ia, also called PMM2-congenital disorder of glycosylation (PMM2-CDG) (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108).
Comment:
NM_000303.2(PMM2):c.422G>A(R141H) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Please note that in the homozygous state, R141H may be associated with fetal demise. Sources cited for classification include the following: PMID 11058895, 9497260, 10854097, 21541725, 9781039, 26488408, 15844218, 10922383, 26014514, and 10386614. Classification of NM_000303.2(PMM2):c.422G>A(R141H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ia (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (891 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated eukaryotic phosphomannomutase domain (DECIPHER). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg141Cys) variant has been classified as likely pathogenic by multiple clinical diagnostic laboratories (ClinVar). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been consistently classified as pathogenic by multiple clinical diagnostic laboratories and is the most common PMM2 pathogenic variant in Northern Europeans (ClinVar, GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 141 of the PMM2 protein (p.Arg141His). This variant is present in population databases (rs28936415, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). It is commonly reported in individuals of European ancestry (PMID: 9497260, 11517108, 19357119, 21541725, 25355454). ClinVar contains an entry for this variant (Variation ID: 7706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Arg141His variant in PMM2 has been reported in several compound heterozygous individuals with congenital disorder of glycosylation type Ia and is one of the most frequent pathogenic variants in patients with this disorder (Matthijs 1997 PMID: 9140401, Matthijs 1998 PMID: 9497260, de Lonlay 2001 PMID: 11134235). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7706) and has been identified in 0.7% (472/61238) of Finnish chromosomes and 0.6% (6521/1152934) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide evidence that this variant causes complete loss of enzyme activity (Vega 2011 PMID: 21541725, Andreotti 2015 PMID: 26488408). The p.Arg141His variant has never been observed in homozygosity, suggesting that the total absence of PMM2 activity is not compatible with life (Matthijs 1998 PMID: 9497260). Computational prediction tools and conservation analyses suggests that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital disorder of glycosylation type Ia. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderate, PP4, PP3.
Comment:
One of the most common pathogenic PMM2 variants reported among European individuals with CDG-1a, but has only been identified in the compound heterozygous state and is predicted to be homozygous lethal (PMID: 11530212, 11517108); Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (PMID: 21541725); This variant is associated with the following publications: (PMID: 25192236, 20981092, 28373276, 28940310, 34670123, 34828263, 22975760, 10700701, 25333069, 21228398, 11530212, 9140401, 19357119, 11517108, 11589167, 27053713, 28139241, 23988505, 25108116, 16376131, 18629883, 19165618, 28425223, 28566178, 28820871, 30609409, 30487145, 30991241, 31474318, 31628766, 31981409, 31980526, 32595772, 32581362, 33580824, 11409861, 34277356, 33960646, 34426522, 32841164, 32064623, 31589614, 33163565, 32874916, 31736265, 33643843, 33204593, 33413482, 21541725, 32860008, 34055813, 33726816, 35279850, 34445196, 36099812, 36239000, 36773065, 35531120, 37541188, 35281664, 31902100, 37301908, 31391289, 26014514, 26488408)
Comment:
This missense variant (c.422G>A, p.Arg141His) has been observed at very low frequency in population databases (gnomAD). It has been reported in the literature (PMID 24424129, 9140401, 30061496). Variant prediction programs suggest a deleterious effect, and functional studies support this (PMID 21541725). This change was found in an affected patient.
Comment:
PMM2: PM3:Very Strong, PM2, PS3:Supporting
Comment:
PP3, PM3_very_strong, PS3
Comment:
The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.422G>A alteration was observed in 0.4% (891/224,376) of total alleles studied, with a frequency of 0.84% (177/21,196) in the European (Finnish) subpopulation. This missense alteration is the most frequent disease-causing PMM2 alteration and has been reported in several populations (Matthijs, 1997; Schollen, 2000; Vuillaumier-Barrot, 2000; Bohles, 2001; Quelhas, 2007). While the p.R141H alteration has been reported in compound heterozygosity with a second alteration in numerous patients with PMM2-related congenital disorder of glycosylation, no patients homozygous for this alteration have been reported, likely because it is a severe mutation and homozygosity would be lethal early in development (Matthijs, 1999). This amino acid position is highly conserved in available vertebrate species. The p.R141 amino acid is a crucial part of the distal phosphate binding site in the cap domain of α-PMM2, and loss of the positive charge at this location would impair substrate binding (Silvaggi, 2006). Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011). The p.R141H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
The PMM2 c.422G>A (p.Arg141His) missense variant is well-documented as the most common pathogenic variant found in patients with PMM2-associated congenital disorders of glycosylation (also known as CDG-1a) (Sparks et al. 2015). The p.Arg141His variant was first described by Matthijs et al. (1997) in a group of 33 unrelated individuals with confirmed phosphomannomutase deficiency. In this study, the p.Arg141His variant was identified in a compound heterozygous state in ten affected individuals. A review by Matthijs et al. (2000) looking at over 249 patients from six different studies and 23 different countries concluded that the p.Arg141His variant accounts for 37 percent of all disease-associated alleles. This variant is typically observed in a compound heterozygous state in patients with severe phenotypes and has never been reported in a homozygous state (Sparks et al. 2015). When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999). The p.Arg141His variant is frequent in most populations and is reported at a frequency of 0.02756 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence the p.Arg141His variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant is found in the compound heterozygous state in approximately 40% of individuals with Congenital disorder of glycosylation Type 1A of European ancestry (PMID: 20301289). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.39% (891/224376). The c.422G>A (p.Arg141His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Functional characterization in multiple studies indicates that the p.Arg141His variant negatively impacts protein function including stability and enzymatic activity (PMID: 21541725, 26488408, 26014514). Based on the available evidence, the c.422G>A (p.Arg141His) variant is classified as Pathogenic.
Comment:
Variant summary: PMM2 c.422G>A (p.Arg141His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 192974 control chromosomes. c.422G>A has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1997, Barone_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of PMM2 enzyme activity in one study (example, Vega_2011) and an oligomerization profile with a predominant aggregate fraction, less dimerization, nearly non-detectable enzymatic activities, and shorter degradation time in another study (example, Yuste-Checa_2015). Thus, variant severly affected both the folding as well as catalytic properties of the PMM2 protein . Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Comment:
The c.422G>A;p.(Arg141His)missense change one of most frequently variant associated with the phenotype described in the gene and ClinVar contains an entry for this variant (ClinVar ID: 7706; PMID: 32860008; 32581362; 31474318; 28940310; 28373276; 25333069; 22975760; 21228398; 19357119; 11530212; 10700701; 9140401) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21541725, 26488408, 26014514) - PS3. The variant is present at low allele frequencies population databases (rs28936415– gnomAD 0.03660%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg141His) was detected in trans with a Pathogenic variant (PMID: 9140401; 9497260; 9781039; 11058895; 11134235; 11517108; 19357119; 20301289; 21541725; 25355454) - PM3_very strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (c.421C>T (p.Arg141Cys) - PMID: 15844218) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Comment:
The PMM2 c.422G>A variant is classified as PATHOGENIC (PM3, PP3, PS3, PS4) The PMM2 c.422G>A variant is a single nucleotide change in exon 5 of the PMM2 gene, which is predicted to change the amino acid arginine at position 141 in the protein to histidine. This is a recurrent variant and one of the most common PMM2 mutations (PS4). It is predicted to be homozygous lethal, so is only found in compound heterozygous state (PM3). Functional studies have demonstrated reduced enzyme stability and catalytic activity compared with wild type (PMID:21541725) (PS3). This variant is in dbSNP (rs28936415) and has been reported in population databases (gnomAD 891/224376 alleles, 0 homozygotes). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (ClinVar Variation ID: 22745). It is also classed as damaging for congenital disorder of glycosylation type 1a in HGMD (CM971228). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.397%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.78). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007706). A different missense change at the same codon (p.Arg141Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550780). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been reported in the literature as a compound heterozygote in several individuals with Congenital disorder of glycosylation type Ia (CDG-Ia) and segregating with disease in affected family members. Of note, at least one publication notes that this variant is the most common pathogenic variant for this condition (Selected publications: Matthijs 1997 PMID:9140401, van Ommenn 2000 PMID:10700701, Briones 2001 PMID:11589167, Kjaergard 2001 PMID:11517108, Barone 2008 PMID:18629883, Vega 2011 PMID:21541725, Bastaki 2018 PMID:28940310). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.7% (82/10618) (https://gnomad.broadinstitute.org/variant/16-8811153-G-A?dataset=gnomad_r3). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID:7706). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies support that this variant will impact the protein by affecting folding and catalytic activity (Vega 2011 PMID:21541725, Yuste-Checa 2015 PMID:26014514). In summary, this variant is classified as pathogenic based on the data above.
Comment:
Criteria applied: PS3,PS4,PM5_SUP,PP3
Comment:
A PMM2 c.422G>A (p.Arg141His) variant was identified in a heterozygous state. This variant has been reported in numerous individuals with PMM2-related congenital disorders of glycosylation (Matthijs G et al., PMID: 9497260; Kjaergaard S et al., PMID: 11517108; Romano S et al., PMID: 19357119; Vega AI et al., PMID: 21541725; Barone R et al., PMID: 25355454; Matthijs G et al., PMID: 9140401; de Lonlay P et al., PMID: 11134235) and is one of the most frequent pathogenic variants in this gene. The PMM2 c.422G>A (p.Arg141His) variant has been reported in the ClinVar database as pathogenic by several submitters (ClinVar ID: 7706). The global population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.4%, which is consistent with the carrier frequency for this disorder based on the recent estimated incidence of disease (Pajusalu S et al., PMID: 34447415). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PMM2 function. In support of this prediction, functional studies show that the p.Arg141His variant affects protein stability, indicating that this variant impacts protein function (Vega AI et al., PMID: 21541725; Yuste-Checa P et al., PMID: 26014514). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Comment:
NM_000303.2:c.422G>A in the PMM2 gene has an allele frequency of 0.008 in European(Finnish) subpopulation in the gnomAD database. Functional studies demonstrate that p.Arg141His has reduced protein stability and enzymatic activity in vitro (PMID: 26014514).It was detected in multiple individuals with autosomal recessive PMM2-CDG, compound heterozygous with c.710C>T (p.Thr237Met), c.484C>T (p.Arg162Trp), c.722G>C (p.Cys241Ser), c.677C>G (p.Thr226Ser) (PMID: 21541725).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PM3_Strong; PS3; PP4
Comment:
The PMM2 p.R141H is one of the most frequent pathogenic variants found to cause congenital disorder of glycosylation type 1a (CDG1a) and is reported in ~40% of European CDG1a cases. This variant has only been found in the compound heterozygous state, suggesting that homozygosity for the p.A141H variant would be lethal (Matthijs_1998_PMID:9497260; Kjaergaard_1998_PMID:9781039). The variant was identified in dbSNP (ID: rs28936415) and ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, Laboratory for Molecular Medicine, Genetic Services Laboratory, University of Chicago and 15 other laboratories). The variant was identified in control databases in 891 of 224376 chromosomes at a frequency of 0.003971 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 177 of 21196 chromosomes (freq: 0.008351), Ashkenazi Jewish in 71 of 9376 chromosomes (freq: 0.007573), European (non-Finnish) in 511 of 94084 chromosomes (freq: 0.005431), Other in 27 of 6220 chromosomes (freq: 0.004341), Latino in 64 of 30676 chromosomes (freq: 0.002086), South Asian in 24 of 25492 chromosomes (freq: 0.000942), African in 15 of 20700 chromosomes (freq: 0.000725), and East Asian in 2 of 16632 chromosomes (freq: 0.00012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.R141 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.422G>A, in exon 5 that results in an amino acid change, p.Arg141His. The p.Arg141His sequence change has been observed in 0.4% of individuals in the gnomAD database, in the heterozygous state, and is regarded as the most common pathogenic variant found in patients with PMM2-related congenital disorders of glycosylation (PMID: 20301289). The p.Arg141His change affects a highly conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Arg141His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has previously been described in an estimated 40% of individuals with PMM2-related congenital disorders of glycosylation (CDG), in the compound heterozygous state with a second variant (PMID: 20301289, 21541725). Functional studies have also demonstrated that the p.Arg141His change reduces protein stability and enzymatic activity in vitro (PMID: 26014514)
Comment:
The PMM2 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141His. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia (CDG-Ia), and is one of the most frequent pathogenic variants reported in the PMM2 gene (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Vega et al. 2011. PubMed ID: 21541725). The c.422G>A (p.Arg141His) variant is also reported as c.425G>A (p.Arg141His) in the literature. Functional in vitro studies on this variant have demonstrated that it severely impacts protein stability and activity (Vega et al. 2011. PubMed ID: 21541725). Additionally, a mouse model (compound heterozygous for variants corresponding to the human p.Arg141His and p.Phe119Leu variants) demonstrated prenatal death and significantly stunted growth in animals due to protein glycosylation deficiencies (Chan et al. 2016. PubMed ID: 27053713). Of note, the c.422G>A variant has been observed with a subpopulation (European) frequency up to ~0.8% in a large database of individuals with unknown phenotype. However, no homozygotes have been reported to date, and the c.422G>A (p.Arg141His) variant is suspected to be embryonically lethal when present in the homozygous state (Matthijs et al. 1998. PubMed ID: 9497260; Thiel et al. 2006. PubMed ID: 16847317). This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/7706/). Taken together, we interpret this variant as pathogenic.
Comment:
Variant interpreted as Pathogenic and reported on 02-19-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Comment:
Variant classified as Pathogenic and reported on 06-29-2018 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| PMM2-CDG. | Adam MP | - | 2021 | PMID: 20301289 |
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Redefining the Etiologic Landscape of Cerebellar Malformations. | Aldinger KA | American journal of human genetics | 2019 | PMID: 31474318 |
| The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers. | Citro V | International journal of molecular sciences | 2018 | PMID: 30061496 |
| Single-center experience of N-linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs. | Bastaki F | Annals of human genetics | 2018 | PMID: 28940310 |
| Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. | Cabezas OR | Journal of the American Society of Nephrology : JASN | 2017 | PMID: 28373276 |
| Heterodimerization of Two Pathological Mutants Enhances the Activity of Human Phosphomannomutase2. | Andreotti G | PloS one | 2015 | PMID: 26488408 |
| The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein. | Yuste-Checa P | Human mutation | 2015 | PMID: 26014514 |
| A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. | Barone R | Journal of neurology | 2015 | PMID: 25355454 |
| Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
| The copper (II) ion as a carrier for the antibiotic capreomycin against Mycobacterium tuberculosis. | Manning T | Bioorganic & medicinal chemistry letters | 2014 | PMID: 24424129 |
| An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
| Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): expression analysis of PMM2-CDG mutations. | Vega AI | Journal of inherited metabolic disease | 2011 | PMID: 21541725 |
| Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
| Conotruncal heart defects in three patients with congenital disorder of glycosylation type Ia (CDG Ia). | Romano S | Journal of medical genetics | 2009 | PMID: 19357119 |
| Congenital disorder of glycosylation type 1a: three siblings with a mild neurological phenotype. | Coman D | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2007 | PMID: 17451957 |
| Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2. | Quelhas D | Annals of human genetics | 2007 | PMID: 17166182 |
| The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a. | Silvaggi NR | The Journal of biological chemistry | 2006 | PMID: 16540464 |
| A new insight into PMM2 mutations in the French population. | Le Bizec C | Human mutation | 2005 | PMID: 15844218 |
| Prepubertal growth in congenital disorder of glycosylation type Ia (CDG-Ia). | Kjaergaard S | Archives of disease in childhood | 2002 | PMID: 12244009 |
| Hyperinsulinaemic hypoglycaemia--leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). | Böhles H | Journal of inherited metabolic disease | 2001 | PMID: 11916319 |
| Balancing N-linked glycosylation to avoid disease. | Freeze HH | Biochimie | 2001 | PMID: 11530212 |
| Congenital disorder of glycosylation type Ia (CDG-Ia): phenotypic spectrum of the R141H/F119L genotype. | Kjaergaard S | Archives of disease in childhood | 2001 | PMID: 11517108 |
| Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations. | Erlandson A | Human genetics | 2001 | PMID: 11409861 |
| A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. | de Lonlay P | Journal of medical genetics | 2001 | PMID: 11134235 |
| Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). | Matthijs G | Human mutation | 2000 | PMID: 11058895 |
| Identification of four novel PMM2 mutations in congenital disorders of glycosylation (CDG) Ia French patients. | Vuillaumier-Barrot S | Journal of medical genetics | 2000 | PMID: 10922383 |
| Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia). | Schollen E | European journal of human genetics : EJHG | 2000 | PMID: 10854097 |
| Carbohydrate-deficient glycoprotein syndrome type 1a: a variant phenotype with borderline cognitive dysfunction, cerebellar hypoplasia, and coagulation disturbances. | van Ommen CH | The Journal of pediatrics | 2000 | PMID: 10700701 |
| Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia). | Matthijs G | Molecular genetics and metabolism | 1999 | PMID: 10527672 |
| Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. | Pirard M | FEBS letters | 1999 | PMID: 10386614 |
| Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1. | Kjaergaard S | European journal of human genetics : EJHG | 1998 | PMID: 9781039 |
| Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. | Matthijs G | American journal of human genetics | 1998 | PMID: 9497260 |
| Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). | Matthijs G | Nature genetics | 1997 | PMID: 9140401 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMM2 | - | - | - | - |
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