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

gnomAD frequency: 0.00001  dbSNP: rs949271895

Total submissions: 5

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