Submissions for variant NM_000303.3(PMM2):c.682G>T (p.Gly228Cys)

dbSNP: rs558826439

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791923	SCV000931192	pathogenic	PMM2-congenital disorder of glycosylation	2023-03-09	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 10527672, 11058895, 23045520, 25192236, 28425223). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly228 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been observed in individuals with PMM2-related conditions (PMID: 11058895, 11058896), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 639185). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 228 of the PMM2 protein (p.Gly228Cys).
CeGaT Center for Human Genetics Tuebingen	RCV001091538	SCV001247657	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000791923	SCV002072518	likely pathogenic	PMM2-congenital disorder of glycosylation	2022-01-06	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM3,PM2_SUP,PM5_SUP,PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791923	SCV004028587	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.682G>T (p.Gly228Cys) 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 was absent in 251268 control chromosomes (gnomAD). c.682G>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (examples: Matthijs_1999, Matthijs_2000, Coorg_2012, Vals_2017 Inci_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23045520, 33960646, 11058895, 10527672, 28425223). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000791923	SCV004205288	pathogenic	PMM2-congenital disorder of glycosylation	2024-02-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001091538	SCV005201475	likely pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 10527672, 33960646, 11058895, 25192236, 28425223, 16009061, 32892177, 23045520, 31307013, 37042760, 35789514)
Natera, Inc.	RCV000791923	SCV002092449	likely pathogenic	PMM2-congenital disorder of glycosylation	2021-03-17	no assertion criteria provided	clinical testing