DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.722G>C, in exon 8 that results in an amino acid change, p.Cys241Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the African population (dbSNP rs80338709). The p.Cys241Ser change has been described in the compound heterozygous state with a second pathogenic mutation in multiple individuals with a mild form of congenital disorder of glycosylation type Ia (CDG Ia) (PMIDs 11715002, 21541725, 28425223, 28566178, 22012410, 10527672). Functional analyses have demonstrated that the p.Cys241Ser change affects folding of the PMM2 protein, leading to abnormal protein aggregation and intermediate residual PMM2 activity (PMIDs 26014514, 21541725). The p.Cys241Ser change affects a moderately conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Cys241Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).
ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.722G>C (p.Cys241Ser)
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.
(20)
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
20
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.722G>C (p.Cys241Ser)
Variation ID: 7717 Accession: VCV000007717.50
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.2 16: 8847806 (GRCh38) [ NCBI UCSC ] 16: 8941663 (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 8, 2024 Aug 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000303.3:c.722G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Cys241Ser missense NC_000016.10:g.8847806G>C NC_000016.9:g.8941663G>C NG_009209.1:g.54994G>C O15305:p.Cys241Ser - Protein change
- C241S
- Other names
- -
- Canonical SPDI
- NC_000016.10:8847805: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 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00021
The Genome Aggregation Database (gnomAD) 0.00027
- 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 (10) |
criteria provided, multiple submitters, no conflicts
|
Mar 12, 2024 | RCV000008156.35 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Aug 8, 2024 | RCV000153745.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 16, 2016 | RCV000623621.10 | |
|
PMM2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Aug 23, 2024 | RCV004755721.1 |
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
(Apr 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610219.1
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
|
|
|
Pathogenic
(Jan 03, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232518.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426500.1
First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020 |
|
|
|
Pathogenic
(Jul 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002067359.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.722G>C, in exon 8 that results in an amino acid change, p.Cys241Ser. This sequence … (more)
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.722G>C, in exon 8 that results in an amino acid change, p.Cys241Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the African population (dbSNP rs80338709). The p.Cys241Ser change has been described in the compound heterozygous state with a second pathogenic mutation in multiple individuals with a mild form of congenital disorder of glycosylation type Ia (CDG Ia) (PMIDs 11715002, 21541725, 28425223, 28566178, 22012410, 10527672). Functional analyses have demonstrated that the p.Cys241Ser change affects folding of the PMM2 protein, leading to abnormal protein aggregation and intermediate residual PMM2 activity (PMIDs 26014514, 21541725). The p.Cys241Ser change affects a moderately conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Cys241Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL). (less)
|
|
|
Pathogenic
(Jun 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004224101.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP1, PP3, PP4, PM2, PM3_strong, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 26, 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: SCV000633728.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 241 of the PMM2 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 241 of the PMM2 protein (p.Cys241Ser). This variant is present in population databases (rs80338709, gnomAD 0.06%). This missense change has been observed in individuals with mild congenital disorder of glycosylation Ia (CDG-Ia) (PMID: 11156536, 11715002, 15844218, 21541725, 25355454). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7717). 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: 11715002, 21541725, 22012410, 26014514). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 26, 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: SCV000696504.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The PMM2 c.722G>C (p.Cys241Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The PMM2 c.722G>C (p.Cys241Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/120396 control chromosomes at a frequency of 0.0000748, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). The variant has been reported in numerous CDG1A patients and has been associated with a mild phenotype. Patient fibroblasts (which also carry a second pathogenic variant) show ~30% residual enzyme activity, and functional studies using expression systems also show <30% residual enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894097.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905596.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Clinical Features:
Cerebellar ataxia (present)
Sex: female
|
|
|
Pathogenic
(Sep 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741806.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Autistic disorder of childhood onset (present) , Congenital cerebellar hypoplasia (present) , Cerebellar ataxia (present) , Muscular hypotonia (present) , … (more)
Global developmental delay (present) , Autistic disorder of childhood onset (present) , Congenital cerebellar hypoplasia (present) , Cerebellar ataxia (present) , Muscular hypotonia (present) , Deeply set eye (present) , Broad chin (present) , Midface retrusion (present) , Downturned corners of mouth (present) , Vesicoureteral reflux (present) , Abnormality of the urethra (present) , Hypermetropia (present) , Esotropia (present) , Constipation (present) , Behavioral abnormality (present) , Anxiety (present) , Aggressive behavior (present) , Gait imbalance (present) , Intention tremor (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: European/Native American
|
|
|
Pathogenic
(Jul 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004024507.2
First in ClinVar: Aug 19, 2023 Last updated: Nov 11, 2023 |
Comment:
This PMM2 variant (rs80338709) is rare (<0.1%) in a large population dataset (gnomAD: 21/282190 total alleles; 0.0074%; no homozygotes) and has been reported in ClinVar. … (more)
This PMM2 variant (rs80338709) is rare (<0.1%) in a large population dataset (gnomAD: 21/282190 total alleles; 0.0074%; no homozygotes) and has been reported in ClinVar. This variant has been reported in compound heterozygous state with a second pathogenic PMM2 variant in unrelated individuals with a mild form of PMM2-CDG. Experimental studies have demonstrated that this amino acid substitution affects folding of the PMM2 protein, leading to abnormal protein aggregation and reduced PMM2 activity. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is likely in trans (on the opposite chromosome) with a second pathogenic PMM2 variant in this individual. We consider c.722G>C (p.Cys241Ser) to be pathogenic for PMM2-CDG. (less)
|
|
|
Pathogenic
(Mar 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204827.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002072677.3
First in ClinVar: Jan 29, 2022 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate C241S reduced enzyme activity and affected folding properties of the PMM2 protein (PMID: 26014514); In silico analysis supports that this missense … (more)
Published functional studies demonstrate C241S reduced enzyme activity and affected folding properties of the PMM2 protein (PMID: 26014514); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33643843, 30293989, 22012410, 21541725, 28425223, 11715002, 28566178, 29482223, 30304743, 31307013, 32630370, 31115488, 33163565, 33413482, 35279850, 35531120, 32860008, 34480478, 33879512, 34828263, 26014514, 10527672) (less)
|
|
|
Pathogenic
(Feb 01, 2001)
|
no assertion criteria provided
Method: literature only
|
CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028361.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2020 |
Comment on evidence:
In a review of PMM2 mutations causing congenital disorder of glycosylation type Ia (CDG1A; 212065), Matthijs et al. (1999) noted that 4 patients had a … (more)
In a review of PMM2 mutations causing congenital disorder of glycosylation type Ia (CDG1A; 212065), Matthijs et al. (1999) noted that 4 patients had a 722G-C change in exon 8, resulting in a cys241-to-ser (C241S) mutation in a nonconserved region in the C-terminal part of the PMM2 protein. Vuillaumier-Barrot et al. (2000) determined that this mutation decreases the activity of PMM2 by only 50%. Grunewald et al. (2001) found that the C241S mutation was present in compound heterozygous state in 6 of 9 patients with a mild form of CDG Ia. Vuillaumier-Barrot et al. (2000) identified the C241S mutation in compound heterozygosity with R141H (601785.0001) in a French patient with CDG Ia. (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: SCV001458208.1
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
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968201.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
|
Pathogenic
(Aug 23, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PMM2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360300.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The PMM2 c.722G>C variant is predicted to result in the amino acid substitution p.Cys241Ser. This variant has been reported as causative for autosomal recessive congenital … (more)
The PMM2 c.722G>C variant is predicted to result in the amino acid substitution p.Cys241Ser. This variant has been reported as causative for autosomal recessive congenital disorder of glycosylation type Ia (Matthijs et al. 1999. PubMed ID: 10527672; Westphal et al. 2001. PubMed ID: 11715002; Vega et al. 2011. PubMed ID: 21541725). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Oct 12, 2016)
|
no assertion criteria provided
Method: clinical testing
|
PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487108.2
First in ClinVar: Oct 11, 2015 Last updated: Aug 13, 2019 |
|
|
|
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: SCV001959832.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
PMM2-congenital disorder of glycosylation
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000040591.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
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Comment:
Comment:
PP1, PP3, PP4, PM2, PM3_strong, PS4_moderate
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 241 of the PMM2 protein (p.Cys241Ser). This variant is present in population databases (rs80338709, gnomAD 0.06%). This missense change has been observed in individuals with mild congenital disorder of glycosylation Ia (CDG-Ia) (PMID: 11156536, 11715002, 15844218, 21541725, 25355454). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7717). 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: 11715002, 21541725, 22012410, 26014514). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The PMM2 c.722G>C (p.Cys241Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/120396 control chromosomes at a frequency of 0.0000748, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). The variant has been reported in numerous CDG1A patients and has been associated with a mild phenotype. Patient fibroblasts (which also carry a second pathogenic variant) show ~30% residual enzyme activity, and functional studies using expression systems also show <30% residual enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This PMM2 variant (rs80338709) is rare (<0.1%) in a large population dataset (gnomAD: 21/282190 total alleles; 0.0074%; no homozygotes) and has been reported in ClinVar. This variant has been reported in compound heterozygous state with a second pathogenic PMM2 variant in unrelated individuals with a mild form of PMM2-CDG. Experimental studies have demonstrated that this amino acid substitution affects folding of the PMM2 protein, leading to abnormal protein aggregation and reduced PMM2 activity. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is likely in trans (on the opposite chromosome) with a second pathogenic PMM2 variant in this individual. We consider c.722G>C (p.Cys241Ser) to be pathogenic for PMM2-CDG.
Comment:
Published functional studies demonstrate C241S reduced enzyme activity and affected folding properties of the PMM2 protein (PMID: 26014514); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33643843, 30293989, 22012410, 21541725, 28425223, 11715002, 28566178, 29482223, 30304743, 31307013, 32630370, 31115488, 33163565, 33413482, 35279850, 35531120, 32860008, 34480478, 33879512, 34828263, 26014514, 10527672)
Comment:
The PMM2 c.722G>C variant is predicted to result in the amino acid substitution p.Cys241Ser. This variant has been reported as causative for autosomal recessive congenital disorder of glycosylation type Ia (Matthijs et al. 1999. PubMed ID: 10527672; Westphal et al. 2001. PubMed ID: 11715002; Vega et al. 2011. PubMed ID: 21541725). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD. This variant is interpreted 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:
DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.722G>C, in exon 8 that results in an amino acid change, p.Cys241Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the African population (dbSNP rs80338709). The p.Cys241Ser change has been described in the compound heterozygous state with a second pathogenic mutation in multiple individuals with a mild form of congenital disorder of glycosylation type Ia (CDG Ia) (PMIDs 11715002, 21541725, 28425223, 28566178, 22012410, 10527672). Functional analyses have demonstrated that the p.Cys241Ser change affects folding of the PMM2 protein, leading to abnormal protein aggregation and intermediate residual PMM2 activity (PMIDs 26014514, 21541725). The p.Cys241Ser change affects a moderately conserved amino acid residue located in a domain of the PMM2 protein that is known to be functional. The p.Cys241Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).
Comment:
PP1, PP3, PP4, PM2, PM3_strong, PS4_moderate
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 241 of the PMM2 protein (p.Cys241Ser). This variant is present in population databases (rs80338709, gnomAD 0.06%). This missense change has been observed in individuals with mild congenital disorder of glycosylation Ia (CDG-Ia) (PMID: 11156536, 11715002, 15844218, 21541725, 25355454). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7717). 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: 11715002, 21541725, 22012410, 26014514). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The PMM2 c.722G>C (p.Cys241Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 9/120396 control chromosomes at a frequency of 0.0000748, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). The variant has been reported in numerous CDG1A patients and has been associated with a mild phenotype. Patient fibroblasts (which also carry a second pathogenic variant) show ~30% residual enzyme activity, and functional studies using expression systems also show <30% residual enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This PMM2 variant (rs80338709) is rare (<0.1%) in a large population dataset (gnomAD: 21/282190 total alleles; 0.0074%; no homozygotes) and has been reported in ClinVar. This variant has been reported in compound heterozygous state with a second pathogenic PMM2 variant in unrelated individuals with a mild form of PMM2-CDG. Experimental studies have demonstrated that this amino acid substitution affects folding of the PMM2 protein, leading to abnormal protein aggregation and reduced PMM2 activity. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is likely in trans (on the opposite chromosome) with a second pathogenic PMM2 variant in this individual. We consider c.722G>C (p.Cys241Ser) to be pathogenic for PMM2-CDG.
Comment:
Published functional studies demonstrate C241S reduced enzyme activity and affected folding properties of the PMM2 protein (PMID: 26014514); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 33643843, 30293989, 22012410, 21541725, 28425223, 11715002, 28566178, 29482223, 30304743, 31307013, 32630370, 31115488, 33163565, 33413482, 35279850, 35531120, 32860008, 34480478, 33879512, 34828263, 26014514, 10527672)
Comment:
The PMM2 c.722G>C variant is predicted to result in the amino acid substitution p.Cys241Ser. This variant has been reported as causative for autosomal recessive congenital disorder of glycosylation type Ia (Matthijs et al. 1999. PubMed ID: 10527672; Westphal et al. 2001. PubMed ID: 11715002; Vega et al. 2011. PubMed ID: 21541725). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| PMM2-CDG. | Adam MP | - | 2021 | PMID: 20301289 |
| Expanding the phenotype of phosphomannomutase-2 gene congenital disorder of glycosylation: Cervical dystonia. | Rossi M | Journal of the neurological sciences | 2017 | PMID: 28566178 |
| Three families with mild PMM2-CDG and normal cognitive development. | Vals MA | American journal of medical genetics. Part A | 2017 | PMID: 28425223 |
| The Effects of PMM2-CDG-Causing Mutations on the Folding, Activity, and Stability of the PMM2 Protein. | Yuste-Checa P | Human mutation | 2015 | PMID: 26014514 |
| A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. | Barone R | Journal of neurology | 2015 | PMID: 25355454 |
| Mild clinical and biochemical phenotype in two patients with PMM2-CDG (congenital disorder of glycosylation Ia). | Casado M | Cerebellum (London, England) | 2012 | PMID: 22012410 |
| 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 |
| Borderline mental development in a congenital disorder of glycosylation (CDG) type Ia patient with multisystemic involvement (intermediate phenotype). | Barone R | Journal of inherited metabolic disease | 2007 | PMID: 17186415 |
| Congenital disorder of glycosylation type Ia: searching for the origin of common mutations in PMM2. | Quelhas D | Annals of human genetics | 2007 | PMID: 17166182 |
| A new insight into PMM2 mutations in the French population. | Le Bizec C | Human mutation | 2005 | PMID: 15844218 |
| Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia. | Westphal V | Genetics in medicine : official journal of the American College of Medical Genetics | 2001 | PMID: 11715002 |
| 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 |
| Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia). | Matthijs G | Molecular genetics and metabolism | 1999 | PMID: 10527672 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMM2 | - | - | - | - |
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Text-mined citations for rs80338709 ...
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Record last updated Nov 10, 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.