ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.58C>T (p.Pro20Ser)

gnomAD frequency: 0.00001  dbSNP: rs949271895
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000850396 SCV000992591 likely pathogenic PMM2-congenital disorder of glycosylation 2019-07-03 criteria provided, single submitter research
Labcorp Genetics (formerly Invitae), Labcorp RCV000850396 SCV001558414 uncertain significance PMM2-congenital disorder of glycosylation 2021-09-08 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 20 of the PMM2 protein (p.Pro20Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 15844218, 20638314). ClinVar contains an entry for this variant (Variation ID: 689645). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002265902 SCV002547964 uncertain significance not specified 2022-05-26 criteria provided, single submitter clinical testing Variant summary: PMM2 c.58C>T (p.Pro20Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 228314 control chromosomes. c.58C>T has been reported in the literature in as a compound heterozygous genotype with c.395T>C (p.Ile132Thr) on the other allele in at-least one individual affected with Congenital Disorder Of Glycosylation Type 1a (example, Le Bizec_2005 cited in Monin_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Disorder Of Glycosylation Type 1a. A co-occurrence in cis with another pathogenic variant(s) has been reported in the individual described above (Le Bizec_2005) and observed at our laboratory (PMM2 c.66+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function for this variant in isolation as expressed in an E Coli system (Li Bizec_2005). The most pronounced variant effect results in approximately 20% of normal PMM2 activity in vitro. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx RCV004789237 SCV005402070 likely pathogenic not provided 2024-05-16 criteria provided, single submitter clinical testing Observed with the c.66+1 G>T variant on the same allele (in cis) as well as another pathogenic variant on the opposite allele (in trans) in patients with features of a congenital disorder of glycosylation in published literature (PMID: 15844218, 20638314, 25497157); Published functional studies demonstrate a damaging effect with decreased enzyme activity (PMID: 15844218); 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: 31420886, 34859900, 34277356, 20638314, 33209585, 25497157, 15844218)
Natera, Inc. RCV000850396 SCV002089461 uncertain significance PMM2-congenital disorder of glycosylation 2020-10-13 no assertion criteria provided clinical testing

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