The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product. The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000860729). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_002435.3(MPI):c.1193T>C (p.Ile398Thr)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002435.3(MPI):c.1193T>C (p.Ile398Thr)
Variation ID: 860729 Accession: VCV000860729.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q24.1 15: 74897651 (GRCh38) [ NCBI UCSC ] 15: 75189992 (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 15, 2020 Jun 17, 2024 Mar 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002435.3:c.1193T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002426.1:p.Ile398Thr missense NM_001289155.2:c.*120T>C 3 prime UTR NM_001289156.2:c.1043T>C NP_001276085.1:p.Ile348Thr missense NM_001289157.2:c.1010T>C NP_001276086.1:p.Ile337Thr missense NM_001330372.2:c.1133T>C NP_001317301.1:p.Ile378Thr missense NC_000015.10:g.74897651T>C NC_000015.9:g.75189992T>C NG_008921.1:g.12583T>C - Protein change
- I378T, I337T, I398T, I348T
- Other names
- -
- Canonical SPDI
- NC_000015.10:74897650:T:C
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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. |
|||
| MPI | - | - |
GRCh38 GRCh37 |
510 | 560 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 29, 2024 | RCV001067096.16 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
MPI-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573371.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product. The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000860729). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hepatosplenomegaly (present) , Ketotic hypoglycemia (present)
|
|
|
Pathogenic
(Apr 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MPI-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929283.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: MPI c.1193T>C (p.Ile398Thr) results in a non-conservative amino acid change located in the Phosphomannose isomerase type I, C-terminal domain (IPR046456) of the encoded … (more)
Variant summary: MPI c.1193T>C (p.Ile398Thr) results in a non-conservative amino acid change located in the Phosphomannose isomerase type I, C-terminal domain (IPR046456) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251494 control chromosomes (gnomAD). c.1193T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1B (example: de la Morena-Barrio_2019, Abdel Ghaffar_2020 and Lipinski_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33643843, 30545931, 33204592).Three 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
(Jun 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MPI-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
unknown
|
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center
Accession: SCV003930385.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
|
|
|
Pathogenic
(Oct 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MPI-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001232132.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 398 of the MPI protein (p.Ile398Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 398 of the MPI protein (p.Ile398Thr). This variant is present in population databases (rs369326210, gnomAD 0.008%). This missense change has been observed in individual(s) with MPI-congenital disorder of glycosylation (CDG-Ib) (PMID: 10484808, 30545931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 860729). 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 not expected to disrupt MPI protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Mar 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
MPI-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004193277.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Likely pathogenic
(Sep 10, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Congenital disorder of glycosylation type 1b
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089795.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Variant summary: MPI c.1193T>C (p.Ile398Thr) results in a non-conservative amino acid change located in the Phosphomannose isomerase type I, C-terminal domain (IPR046456) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251494 control chromosomes (gnomAD). c.1193T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1B (example: de la Morena-Barrio_2019, Abdel Ghaffar_2020 and Lipinski_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33643843, 30545931, 33204592).Three 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:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 398 of the MPI protein (p.Ile398Thr). This variant is present in population databases (rs369326210, gnomAD 0.008%). This missense change has been observed in individual(s) with MPI-congenital disorder of glycosylation (CDG-Ib) (PMID: 10484808, 30545931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 860729). 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 not expected to disrupt MPI protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
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 variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product. The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000860729). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Variant summary: MPI c.1193T>C (p.Ile398Thr) results in a non-conservative amino acid change located in the Phosphomannose isomerase type I, C-terminal domain (IPR046456) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251494 control chromosomes (gnomAD). c.1193T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1B (example: de la Morena-Barrio_2019, Abdel Ghaffar_2020 and Lipinski_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33643843, 30545931, 33204592).Three 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:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 398 of the MPI protein (p.Ile398Thr). This variant is present in population databases (rs369326210, gnomAD 0.008%). This missense change has been observed in individual(s) with MPI-congenital disorder of glycosylation (CDG-Ib) (PMID: 10484808, 30545931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 860729). 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 not expected to disrupt MPI protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Congenital disorders of glycosylation: Prevalence, incidence and mutational spectrum in the Polish population. | Lipiński P | Molecular genetics and metabolism reports | 2021 | PMID: 33643843 |
| MPI-CDG from a hepatic perspective: Report of two Egyptian cases and review of literature. | Abdel Ghaffar TY | JIMD reports | 2020 | PMID: 33204592 |
| MPI-CDG with transient hypoglycosylation and antithrombin deficiency. | de la Morena-Barrio ME | Haematologica | 2019 | PMID: 30545931 |
| Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: A new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose. | de Lonlay P | The Journal of pediatrics | 1999 | PMID: 10484808 |
Text-mined citations for rs369326210 ...
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 Sep 29, 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.