ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.623G>C (p.Gly208Ala) (rs398123309)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790723 SCV000232042 pathogenic not provided 2013-02-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000179744 SCV000696501 pathogenic Congenital disorder of glycosylation, type Ia 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 Congenital disorder of glycosylation, type Ia 2017-02-24 criteria provided, single submitter clinical testing
Invitae RCV000179744 SCV000948400 pathogenic Congenital disorder of glycosylation, type Ia 2019-05-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 208 of the PMM2 protein (p.Gly208Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs398123309, ExAC 0.001%). This variant has been observed to be homozygous or in combination with another PMM2 variant in several individuals affected with PMM2-CDG (PMID: 9497260, 10801058, 15277997, 24037084). ClinVar contains an entry for this variant (Variation ID: 92804). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Congenital disorder of glycosylation, type Ia 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.

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