Submissions for variant NM_000303.3(PMM2):c.623G>C (p.Gly208Ala)

gnomAD frequency: 0.00001  dbSNP: rs398123309

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000790723	SCV000232042	pathogenic	not provided	2013-02-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179744	SCV000696501	pathogenic	PMM2-congenital disorder of glycosylation	2016-05-16	criteria provided, single submitter	clinical testing	Variant summary: The PMM2 c.623G>C (p.Gly208Ala) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome. This variant was found in 1/121408 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.005902). This variant has been reported in multiple CDG1A patients homozygously or as a compound heterozygotes with a pathogenic variant (such as R141H) in trans. All reported patients had very low level of PMM activity detected. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Considering all, this variant is classified as pathogenic.
Counsyl	RCV000179744	SCV000789849	likely pathogenic	PMM2-congenital disorder of glycosylation	2017-02-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179744	SCV000948400	pathogenic	PMM2-congenital disorder of glycosylation	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 208 of the PMM2 protein (p.Gly208Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 10801058, 15277997, 24037084). ClinVar contains an entry for this variant (Variation ID: 92804). 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%. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000179744	SCV000996185	likely pathogenic	PMM2-congenital disorder of glycosylation	2018-08-13	criteria provided, single submitter	clinical testing	This variant has been previously reported in the compound heterozygous state in individuals with Congenital disorder of glycosylation Type 1A (PMID: 9497260, 19396570, 10801058) and has been classified as pathogenic and likely pathogenic by multiple clinical diagnostic laboratories in ClinVar (Variation ID: 92804). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.623G>C (p.Gly208Ala) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.623G>C (p.Gly208Ala) variant is classified as Likely Pathogenic.
Baylor Genetics	RCV000179744	SCV004205263	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-12-24	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000179744	SCV005086337	pathogenic	PMM2-congenital disorder of glycosylation	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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 congenital disorder of glycosylation, type Ia (MIM#212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The clinical manifestations and course are highly variable, ranging from infants who pass away in the first year of life to mildly affected adults (PMID: 20301289). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 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 eukaryotic phosphomannomutase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with CDG who also had another PMM2 variant, three of whom were known to be compound heterozygous (PMIDs: 22649348, 10801058, 28122681, 30397276). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV000179744	SCV001457178	pathogenic	PMM2-congenital disorder of glycosylation	2020-09-16	no assertion criteria provided	clinical testing