ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.203T>G (p.Phe68Cys)

dbSNP: rs373788015
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Morava/Kozicz Lab, Department of Clinical Genomics, Mayo Clinic RCV001849246 SCV002106380 uncertain significance PMM2-congenital disorder of glycosylation 2020-02-17 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 68 of the PMM2 protein (p.Phe68Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine (PP3). In addition, this variant is absent in the normal population (C=0.00000 (0/14050, ALFA)) (PM2). SIFT, PolyPhen2 and Align-GCGD all suggest that the variant is likely damaging (PP3). Patient has another pathogenic variant in the same gene (PMM2 p.Arg141His). Missense variants in nearby residues reported as pathogenic in individuals with PMM2-CDG (PP2). Patient's phenotype is consistent with PMM2-CDG diagnosis (PP4). Though there is a lot of supporting evidence, at this time there is insufficient evidence to clearly evaluate this variant. Therefore, we classify it as a VUS.
Labcorp Genetics (formerly Invitae), Labcorp RCV001849246 SCV002265068 pathogenic PMM2-congenital disorder of glycosylation 2023-09-08 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital disorders of glycosylation (PMID: 34652821; Invitae). 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: 1344574). 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. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 68 of the PMM2 protein (p.Phe68Cys).

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