NM_000303.2(PMM2):c.691G>A(V231M) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 15844218 and 10386614. Classification of NM_000303.2(PMM2):c.691G>A(V231M) 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.
ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.691G>A (p.Val231Met)
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.
(19)
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
19
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.691G>A (p.Val231Met)
Variation ID: 7719 Accession: VCV000007719.59
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.2 16: 8847775 (GRCh38) [ NCBI UCSC ] 16: 8941632 (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 Oct 20, 2024 Mar 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000303.3:c.691G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Val231Met missense NC_000016.10:g.8847775G>A NC_000016.9:g.8941632G>A NG_009209.1:g.54963G>A O15305:p.Val231Met - Protein change
- V231M
- Other names
-
Chr16: 8847775
- Canonical SPDI
- NC_000016.10:8847774:G:A
-
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) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
- 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 |
776 | 875 | |
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 (14) |
criteria provided, multiple submitters, no conflicts
|
Mar 18, 2024 | RCV000008158.40 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 16, 2022 | RCV000790822.38 |
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
(Jun 12, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232516.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 12
Sex: mixed
|
|
|
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: SCV000998568.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
|
Pathogenic
(Dec 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193990.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000303.2(PMM2):c.691G>A(V231M) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 15844218 … (more)
NM_000303.2(PMM2):c.691G>A(V231M) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 15844218 and 10386614. Classification of NM_000303.2(PMM2):c.691G>A(V231M) 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)
|
|
|
Pathogenic
(Sep 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV002574830.1
First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022 |
Clinical Features:
Global developmental delay (present) , Dandy-Walker malformation (present) , Cerebellar hypoplasia (present) , Hypoplasia of the corpus callosum (present) , Interictal epileptiform activity (present)
Sex: female
Tissue: Blood
|
|
|
Pathogenic
(Dec 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002795991.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Aug 21, 2017)
|
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: SCV000696502.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The PMM2 c.691G>A (p.Val231Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The PMM2 c.691G>A (p.Val231Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/120856 control chromosomes at a frequency of 0.0000579, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many pts/families with evidence of co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 15, 2018)
|
criteria provided, single submitter
Method: research
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001132559.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
Comment:
The homozygous p.Val231Met variant in PMM2 was identified by our study in two siblings with Congenital Disorder of Glycosylation. The p.Val231Met variant is pathogenic based … (more)
The homozygous p.Val231Met variant in PMM2 was identified by our study in two siblings with Congenital Disorder of Glycosylation. The p.Val231Met variant is pathogenic based off of multiple reports in ClinVar and the literature. (less)
Clinical Features:
Abnormality of brain morphology (present)
|
|
|
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: SCV001435296.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Number of individuals with the variant: 1
Family history: no
Sex: male
Secondary finding: no
|
|
|
Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768393.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.2, 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_v1.3.2, 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 PMM2-congenital disorder of glycosylation (PMM2-CDG). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PMM domain (NCBI, Decipher, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as pathogenic in patients with PMM2-CDG (ClinVar, LOVD, PMID: 28425223, 30397276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001738). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jun 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001780554.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that the V231M variant results in decreased enzymatic activity and thermal stability (Pirard et al., 1999); In silico analysis supports that … (more)
Published functional studies demonstrate that the V231M variant results in decreased enzymatic activity and thermal stability (Pirard et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9497260, 23430838, 25355454, 31981409, 18203160, 22975760, 19168813, 9140401, 15714316, 10386614, 10801058, 10922383, 28425223, 15844218, 11409861, 31589614, 33643843, 33133147, 33413482, 31319225, 33726816, Vignogna2022[preprint], 34420056) (less)
|
|
|
Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004013362.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PM3_Very Strong, PS3, PM1, PM2, PP3
|
|
|
Pathogenic
(Jan 19, 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: SCV000633726.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the PMM2 protein (p.Val231Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the PMM2 protein (p.Val231Met). This variant is present in population databases (rs80338707, gnomAD 0.01%). This missense change has been observed in individual(s) with PMM2-CDG, being one of the most common causes of the disease in European populations (PMID: 9497260, 10801058, 15844218, 23430838, 25355454). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7719). 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: 10386614). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204833.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Dec 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248282.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Aug 01, 2000)
|
no assertion criteria provided
Method: literature only
|
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028363.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015 |
Comment on evidence:
In 3 of 22 chromosomes in French patients with congenital disorder of glycosylation type I (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified a 691G-A transition … (more)
In 3 of 22 chromosomes in French patients with congenital disorder of glycosylation type I (CDG1A; 212065), Vuillaumier-Barrot et al. (2000) identified a 691G-A transition in exon 8 in the PMM2 gene, resulting in a val231-to-met (V231M) substitution. All patients were compound heterozygous for V231M and R141H (601785.0001). (less)
|
|
|
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: SCV001458207.1
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:
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: SCV001952223.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740452.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
PMM2-congenital disorder of glycosylation
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000040589.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
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Comment:
Comment:
Variant summary: The PMM2 c.691G>A (p.Val231Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/120856 control chromosomes at a frequency of 0.0000579, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many pts/families with evidence of co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The homozygous p.Val231Met variant in PMM2 was identified by our study in two siblings with Congenital Disorder of Glycosylation. The p.Val231Met variant is pathogenic based off of multiple reports in ClinVar and the literature.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.2, 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 PMM2-congenital disorder of glycosylation (PMM2-CDG). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PMM domain (NCBI, Decipher, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as pathogenic in patients with PMM2-CDG (ClinVar, LOVD, PMID: 28425223, 30397276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001738). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Published functional studies demonstrate that the V231M variant results in decreased enzymatic activity and thermal stability (Pirard et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9497260, 23430838, 25355454, 31981409, 18203160, 22975760, 19168813, 9140401, 15714316, 10386614, 10801058, 10922383, 28425223, 15844218, 11409861, 31589614, 33643843, 33133147, 33413482, 31319225, 33726816, Vignogna2022[preprint], 34420056)
Comment:
PM3_Very Strong, PS3, PM1, PM2, PP3
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the PMM2 protein (p.Val231Met). This variant is present in population databases (rs80338707, gnomAD 0.01%). This missense change has been observed in individual(s) with PMM2-CDG, being one of the most common causes of the disease in European populations (PMID: 9497260, 10801058, 15844218, 23430838, 25355454). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7719). 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: 10386614). 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:
NM_000303.2(PMM2):c.691G>A(V231M) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 15844218 and 10386614. Classification of NM_000303.2(PMM2):c.691G>A(V231M) 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:
Variant summary: The PMM2 c.691G>A (p.Val231Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/120856 control chromosomes at a frequency of 0.0000579, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many pts/families with evidence of co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The homozygous p.Val231Met variant in PMM2 was identified by our study in two siblings with Congenital Disorder of Glycosylation. The p.Val231Met variant is pathogenic based off of multiple reports in ClinVar and the literature.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.2, 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 PMM2-congenital disorder of glycosylation (PMM2-CDG). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PMM domain (NCBI, Decipher, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as pathogenic in patients with PMM2-CDG (ClinVar, LOVD, PMID: 28425223, 30397276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001738). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Published functional studies demonstrate that the V231M variant results in decreased enzymatic activity and thermal stability (Pirard et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9497260, 23430838, 25355454, 31981409, 18203160, 22975760, 19168813, 9140401, 15714316, 10386614, 10801058, 10922383, 28425223, 15844218, 11409861, 31589614, 33643843, 33133147, 33413482, 31319225, 33726816, Vignogna2022[preprint], 34420056)
Comment:
PM3_Very Strong, PS3, PM1, PM2, PP3
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the PMM2 protein (p.Val231Met). This variant is present in population databases (rs80338707, gnomAD 0.01%). This missense change has been observed in individual(s) with PMM2-CDG, being one of the most common causes of the disease in European populations (PMID: 9497260, 10801058, 15844218, 23430838, 25355454). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7719). 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: 10386614). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PMM2-CDG. | Adam MP | - | 2021 | PMID: 20301289 |
| Ten years of screening for congenital disorders of glycosylation in Argentina: case studies and pitfalls. | Asteggiano CG | Pediatric research | 2018 | PMID: 30397276 |
| Three families with mild PMM2-CDG and normal cognitive development. | Vals MA | American journal of medical genetics. Part A | 2017 | PMID: 28425223 |
| Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG). | García-López R | PloS one | 2016 | PMID: 27415628 |
| 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 |
| The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations. | Pérez B | JIMD reports | 2011 | PMID: 23430838 |
| A new insight into PMM2 mutations in the French population. | Le Bizec C | Human mutation | 2005 | PMID: 15844218 |
| Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. | Aronica E | Acta neuropathologica | 2005 | PMID: 15714316 |
| 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 |
| 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 |
| 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 |
| Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1. | Imtiaz F | Journal of inherited metabolic disease | 2000 | PMID: 10801058 |
| Effect of mutations found in carbohydrate-deficient glycoprotein syndrome type IA on the activity of phosphomannomutase 2. | Pirard M | FEBS letters | 1999 | PMID: 10386614 |
| 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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Text-mined citations for rs80338707 ...
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 Nov 03, 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.