Submissions for variant NM_000303.3(PMM2):c.691G>A (p.Val231Met)

gnomAD frequency: 0.00004  dbSNP: rs80338707

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790822	SCV000232516	pathogenic	not provided	2017-06-12	criteria provided, single submitter	clinical testing
Invitae	RCV000008158	SCV000633726	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the PMM2 protein (p.Val231Met). This variant is present in population databases (rs80338707, gnomAD 0.01%). This missense change has been observed in individual(s) with PMM2-CDG, being one of the most common causes of the disease in European populations (PMID: 9497260, 10801058, 15844218, 23430838, 25355454). 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: 7719). 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: 10386614). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000008158	SCV000696502	pathogenic	PMM2-congenital disorder of glycosylation	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The PMM2 c.691G>A (p.Val231Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/120856 control chromosomes at a frequency of 0.0000579, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many pts/families with evidence of co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Pediatric Metabolic Diseases, Hacettepe University	RCV000008158	SCV000998568	pathogenic	PMM2-congenital disorder of glycosylation		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000008158	SCV001132559	pathogenic	PMM2-congenital disorder of glycosylation	2018-11-15	criteria provided, single submitter	research	The homozygous p.Val231Met variant in PMM2 was identified by our study in two siblings with Congenital Disorder of Glycosylation. The p.Val231Met variant is pathogenic based off of multiple reports in ClinVar and the literature.
Myriad Genetics, Inc.	RCV000008158	SCV001193990	pathogenic	PMM2-congenital disorder of glycosylation	2019-12-20	criteria provided, single submitter	clinical testing	NM_000303.2(PMM2):c.691G>A(V231M) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 15844218 and 10386614. Classification of NM_000303.2(PMM2):c.691G>A(V231M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000790822	SCV001248282	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000008158	SCV001435296	pathogenic	PMM2-congenital disorder of glycosylation	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000790822	SCV001780554	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the V231M variant results in decreased enzymatic activity and thermal stability (Pirard et al., 1999); 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: 9497260, 23430838, 25355454, 31981409, 18203160, 22975760, 19168813, 9140401, 15714316, 10386614, 10801058, 10922383, 28425223, 15844218, 11409861, 31589614, 33643843, 33133147, 33413482, 31319225, 33726816, Vignogna2022[preprint], 34420056)
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000008158	SCV002574830	pathogenic	PMM2-congenital disorder of glycosylation	2022-09-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008158	SCV002768393	pathogenic	PMM2-congenital disorder of glycosylation	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PMM2-congenital disorder of glycosylation (PMM2-CDG). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated PMM domain (NCBI, Decipher, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as pathogenic in patients with PMM2-CDG (ClinVar, LOVD, PMID: 28425223, 30397276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001738). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000008158	SCV002795991	pathogenic	PMM2-congenital disorder of glycosylation	2021-12-22	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000008158	SCV004013362	pathogenic	PMM2-congenital disorder of glycosylation	2023-04-11	criteria provided, single submitter	clinical testing	PM3_Very Strong, PS3, PM1, PM2, PP3
Baylor Genetics	RCV000008158	SCV004204833	pathogenic	PMM2-congenital disorder of glycosylation	2023-10-24	criteria provided, single submitter	clinical testing
OMIM	RCV000008158	SCV000028363	pathogenic	PMM2-congenital disorder of glycosylation	2000-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000008158	SCV000040589	not provided	PMM2-congenital disorder of glycosylation		no assertion provided	literature only
Natera, Inc.	RCV000008158	SCV001458207	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000790822	SCV001740452	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000790822	SCV001952223	pathogenic	not provided		no assertion criteria provided	clinical testing