Submissions for variant NM_000303.3(PMM2):c.620T>C (p.Phe207Ser)

gnomAD frequency: 0.00001  dbSNP: rs532870929

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169562	SCV000221058	likely pathogenic	PMM2-congenital disorder of glycosylation	2015-01-22	criteria provided, single submitter	literature only
Baylor Genetics	RCV000169562	SCV001163405	pathogenic	PMM2-congenital disorder of glycosylation	2024-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169562	SCV001578739	pathogenic	PMM2-congenital disorder of glycosylation	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 207 of the PMM2 protein (p.Phe207Ser). This variant is present in population databases (rs532870929, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia or with related clinical features (PMID: 12705494, 19396570, 21541725, 28373276). ClinVar contains an entry for this variant (Variation ID: 189141). 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: 21541725). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169562	SCV002793045	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169562	SCV003844685	pathogenic	PMM2-congenital disorder of glycosylation	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.620T>C (p.Phe207Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251474 control chromosomes. c.620T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (eg. Cabezas_2017, Francisco_2020, Parrado_2022, etc). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Vega_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000169562	SCV002089491	pathogenic	PMM2-congenital disorder of glycosylation	2021-07-19	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755787	SCV005359901	likely pathogenic	PMM2-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The PMM2 c.620T>C variant is predicted to result in the amino acid substitution p.Phe207Ser. This variant has been reported along with a second heterozygous PMM2 variant in multiple individuals with congenital disorder of glycosylation type 1a (Briones et al. 2002. PubMed ID: 12705494; Shanti et al. 2009. PubMed ID: 19396570; Vega et al. 2011. PubMed ID: 21541725). It has also been reported in the compound heterozygous state with a pathogenic variant in the PMM2 promoter region (c.-167G>T) in two members of a single family with hyperinsulemic hypoglycemia and polycystic kidney disease (Cabezas et al. 2017. PubMed ID: 28373276). In vitro experimental studies have shown this variant causes protein misfolding and structural instability, resulting in rapid degradation and a complete loss of enzymatic activity (Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/). This variant is interpreted as likely pathogenic.