Variant summary: PMM2 c.131T>C (p.Val44Ala) results in a non-conservative amino acid change located in the Phosphomannomutase domain (IPR005002) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249792 control chromosomes. c.131T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1998, Grunwald_2001, Vega_2011, Izquierdo-Serra_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity and characterization as a misfolding defect resulting in protein destabilization (example, Vega_2011, Yuste-Checa_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.131T>C (p.Val44Ala)
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_000303.3(PMM2):c.131T>C (p.Val44Ala)
Variation ID: 7725 Accession: VCV000007725.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.2 16: 8801863 (GRCh38) [ NCBI UCSC ] 16: 8895720 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 24, 2015 Feb 14, 2024 May 31, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000303.3:c.131T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Val44Ala missense NC_000016.10:g.8801863T>C NC_000016.9:g.8895720T>C NG_009209.1:g.9051T>C NG_033146.1:g.786A>G O15305:p.Val44Ala - Protein change
- V44A
- Other names
- -
- Canonical SPDI
- NC_000016.10:8801862:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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. |
|||
| PMM2 | - | - |
GRCh38 GRCh37 |
777 | 876 | |
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
|
May 31, 2023 | RCV000008164.15 |
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
(Jun 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital disorder of glycosylation, type Ia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001372414.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: PMM2 c.131T>C (p.Val44Ala) results in a non-conservative amino acid change located in the Phosphomannomutase domain (IPR005002) of the encoded protein sequence. Five of … (more)
Variant summary: PMM2 c.131T>C (p.Val44Ala) results in a non-conservative amino acid change located in the Phosphomannomutase domain (IPR005002) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249792 control chromosomes. c.131T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1998, Grunwald_2001, Vega_2011, Izquierdo-Serra_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity and characterization as a misfolding defect resulting in protein destabilization (example, Vega_2011, Yuste-Checa_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000486888.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Aug 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002233246.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). Algorithms … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7725). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 9497260, 21541725). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 44 of the PMM2 protein (p.Val44Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. (less)
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|
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Pathogenic
(May 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004205280.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
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Pathogenic
(Apr 01, 2007)
|
no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028369.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2020 |
Comment on evidence:
In a patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Schollen et al. (2007) detected compound heterozygosity for a val44-to-ala (V44A) mutation in … (more)
In a patient with congenital disorder of glycosylation type Ia (CDG1A; 212065), Schollen et al. (2007) detected compound heterozygosity for a val44-to-ala (V44A) mutation in PMM2 arising from a 131T-C transition in exon 2, and a large deletion (601785.0021). (less)
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|
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Pathogenic
(Mar 22, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Congenital disorder of glycosylation type 1a
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089468.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7725). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 9497260, 21541725). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 44 of the PMM2 protein (p.Val44Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.
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:
Variant summary: PMM2 c.131T>C (p.Val44Ala) results in a non-conservative amino acid change located in the Phosphomannomutase domain (IPR005002) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249792 control chromosomes. c.131T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (example, Matthijs_1998, Grunwald_2001, Vega_2011, Izquierdo-Serra_2018). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity and characterization as a misfolding defect resulting in protein destabilization (example, Vega_2011, Yuste-Checa_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7725). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 9497260, 21541725). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 44 of the PMM2 protein (p.Val44Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy. | Izquierdo-Serra M | International journal of molecular sciences | 2018 | PMID: 29470411 |
| 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 |
| 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 |
| Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. | Schollen E | Molecular genetics and metabolism | 2007 | PMID: 17307006 |
| High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). | Grünewald S | American journal of human genetics | 2001 | PMID: 11156536 |
| 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 |
Text-mined citations for rs104894534 ...
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.