For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 3243). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 15792865, 28097321, 30426380). This variant is present in population databases (rs119462982, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 200 of the POMT1 protein (p.Ala200Pro).
ClinVar Genomic variation as it relates to human health
NM_001077365.2(POMT1):c.598G>C (p.Ala200Pro)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001077365.2(POMT1):c.598G>C (p.Ala200Pro)
Variation ID: 3243 Accession: VCV000003243.58
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.13 9: 131509801 (GRCh38) [ NCBI UCSC ] 9: 134385188 (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 Jun 28, 2015 Oct 20, 2024 Jan 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001077365.2:c.598G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001070833.1:p.Ala200Pro missense NM_001077366.2:c.436G>C NP_001070834.1:p.Ala146Pro missense NM_001136113.2:c.598G>C NP_001129585.1:p.Ala200Pro missense NM_001136114.2:c.247G>C NP_001129586.1:p.Ala83Pro missense NM_001353193.2:c.598G>C NP_001340122.2:p.Ala200Pro missense NM_001353194.2:c.436G>C NP_001340123.1:p.Ala146Pro missense NM_001353195.2:c.247G>C NP_001340124.1:p.Ala83Pro missense NM_001353196.2:c.508G>C NP_001340125.1:p.Ala170Pro missense NM_001353197.2:c.436G>C NP_001340126.2:p.Ala146Pro missense NM_001353198.2:c.436G>C NP_001340127.2:p.Ala146Pro missense NM_001353199.2:c.247G>C NP_001340128.2:p.Ala83Pro missense NM_001353200.2:c.142G>C NP_001340129.1:p.Ala48Pro missense NM_001374689.1:c.436G>C NP_001361618.1:p.Ala146Pro missense NM_001374690.1:c.598G>C NP_001361619.1:p.Ala200Pro missense NM_001374691.1:c.247G>C NP_001361620.1:p.Ala83Pro missense NM_001374692.1:c.247G>C NP_001361621.1:p.Ala83Pro missense NM_001374693.1:c.436G>C NP_001361622.1:p.Ala146Pro missense NM_001374695.1:c.142G>C NP_001361624.1:p.Ala48Pro missense NM_007171.3:c.598G>C NM_007171.4:c.598G>C NP_009102.4:p.Ala200Pro missense NR_148391.2:n.632G>C non-coding transcript variant NR_148392.2:n.784G>C non-coding transcript variant NR_148393.2:n.632G>C non-coding transcript variant NR_148394.2:n.520G>C non-coding transcript variant NR_148395.2:n.784G>C non-coding transcript variant NR_148396.2:n.413G>C non-coding transcript variant NR_148397.2:n.677G>C non-coding transcript variant NR_148398.2:n.632G>C non-coding transcript variant NR_148399.2:n.1024G>C non-coding transcript variant NR_148400.2:n.618G>C non-coding transcript variant NC_000009.12:g.131509801G>C NC_000009.11:g.134385188G>C NG_008896.1:g.11900G>C LRG_842t1:c.598G>C LRG_842p1:p.Ala200Pro LRG_842t2:c.598G>C LRG_842p2:p.Ala200Pro Q9Y6A1:p.Ala200Pro - Protein change
- A200P, A170P, A48P, A146P, A83P
- Other names
- -
- Canonical SPDI
- NC_000009.12:131509800:G:C
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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. |
|||
| POMT1 | - | - |
GRCh38 GRCh37 |
1164 | 1205 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2024 | RCV000003399.7 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2023 | RCV000179928.28 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2020 | RCV001264826.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001813942.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2023 | RCV001385876.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 3, 2023 | RCV003234890.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV003472966.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Feb 27, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232248.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755602.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
|
Likely pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238600.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1
Walker-Warburg congenital muscular dystrophy Autosomal recessive limb-girdle muscular dystrophy type 2K
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001585884.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 3243). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 15792865, 28097321, 30426380). This variant is present in population databases (rs119462982, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 200 of the POMT1 protein (p.Ala200Pro). (less)
|
|
|
Likely pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204061.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Mar 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
biparental
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001443023.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS4_Moderate,PM2,PM3
Clinical Features:
very severe ID (present) , microcephaly (present) , constipation (present) , cerebral atrophy (present)
|
|
|
Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2K
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058437.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003243, PS1_S). In silico … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003243, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.831, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Generalized hypotonia (present)
|
|
|
Pathogenic
(May 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933874.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: POMT1 c.598G>C (p.Ala200Pro) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of the encoded protein … (more)
Variant summary: POMT1 c.598G>C (p.Ala200Pro) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of 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 8e-06 in 251496 control chromosomes (gnomAD). c.598G>C has been reported in the literature in multiple homozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Geis_2019). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 31311558). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2K
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005091062.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
PM2, PM3, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein … (more)
PM2, PM3, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Muscular dystrophy. (PMID:31311558). (less)
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334771.25
First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 01, 2005)
|
no assertion criteria provided
Method: literature only
|
MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023557.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 28, 2018 |
Comment on evidence:
In 5 unrelated Turkish patients with limb-girdle muscular dystrophy and mental retardation (MDDGC1; 609308), some of whom were described by Dincer et al. (2003), Balci … (more)
In 5 unrelated Turkish patients with limb-girdle muscular dystrophy and mental retardation (MDDGC1; 609308), some of whom were described by Dincer et al. (2003), Balci et al. (2005) identified a homozygous 598G-C transversion in exon 7 of the POMT1 gene, resulting in an ala200-to-pro (A200P) substitution in a highly conserved residue in loop 4 of a cytoplasmic domain of the protein. All patients were born of consanguineous parents. The mutation was not identified in 212 control chromosomes. Balci et al. (2005) noted that A200P was the first reported POMT1 mutation within the cytoplasmic domain and that the phenotype associated with this mutation is significantly milder than Walker-Warburg syndrome (MDDGA1; 236670), which is caused by other POMT1 mutations (see, e.g., 607423.0001). Most significantly, none of the patients with the A200P mutation had structural brain abnormalities on imaging that would signify a cortical migration defect. Haplotype analysis indicated that A200P is a common founder mutation. (less)
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS4_Moderate,PM2,PM3
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003243, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.831, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: POMT1 c.598G>C (p.Ala200Pro) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of 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 8e-06 in 251496 control chromosomes (gnomAD). c.598G>C has been reported in the literature in multiple homozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Geis_2019). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 31311558). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PM2, PM3, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Muscular dystrophy. (PMID:31311558).
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:
For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 3243). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 15792865, 28097321, 30426380). This variant is present in population databases (rs119462982, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 200 of the POMT1 protein (p.Ala200Pro).
Comment:
Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS4_Moderate,PM2,PM3
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003243, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.831, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: POMT1 c.598G>C (p.Ala200Pro) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of 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 8e-06 in 251496 control chromosomes (gnomAD). c.598G>C has been reported in the literature in multiple homozygous individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Geis_2019). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 31311558). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PM2, PM3, PP3, PP5 - Low frequency in gnomAD population databases. In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. This variant has been previously reported as causative for Muscular dystrophy. (PMID:31311558).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical long-time course, novel mutations and genotype-phenotype correlation in a cohort of 27 families with POMT1-related disorders. | Geis T | Orphanet journal of rare diseases | 2019 | PMID: 31311558 |
| Comparison of clinical parameters with whole exome sequencing analysis results of autosomal recessive patients; a center experience. | Elmas M | Molecular biology reports | 2019 | PMID: 30426380 |
| Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. | Reuter MS | JAMA psychiatry | 2017 | PMID: 28097321 |
| Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. | Godfrey C | Brain : a journal of neurology | 2007 | PMID: 17878207 |
| An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. | Balci B | Neuromuscular disorders : NMD | 2005 | PMID: 15792865 |
| A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan. | Dinçer P | Neuromuscular disorders : NMD | 2003 | PMID: 14678799 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POMT1 | - | - | - | - |
Text-mined citations for rs119462982 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.