Submissions for variant NM_000169.3(GLA):c.966C>A (p.Asp322Glu)

dbSNP: rs398123226

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000367678	SCV000331016	pathogenic	not provided	2018-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780289	SCV000917440	pathogenic	Fabry disease	2018-02-21	criteria provided, single submitter	clinical testing	Variant summary: GLA c.966C>A (p.Asp322Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 87728 control chromosomes. c.966C>A has been reported in the literature in multiple individuals affected with Fabry Disease,including largre family with co-segregation (Adalsteinsdottir_2017). 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 leukocyte -GalA activity was less than 10% in all affected male family members reported in Adalsteinsdottir, 2017. In addition, another alteration of the same nucleotide, c.966C>G, leading to the same protein change, p.D322E, was reported in pt presented with classical FD (Lee, 2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000780289	SCV001590649	pathogenic	Fabry disease	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 322 of the GLA protein (p.Asp322Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 28798024). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 222459). 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 GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 28798024). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000780289	SCV002054391	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
deCODE genetics, Amgen	RCV000780289	SCV004022207	likely pathogenic	Fabry disease	2023-07-21	no assertion criteria provided	research	The variant NM_000169.3:c.966C>A (chrX:101398403) in GLA was detected in 2 heterozygous females and 4 hemizygous males out of 58K WGS Icelanders (MAF= 0,009%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes, 3 imputed hemizygotes) we observed an association with hypertrophic cardiomyopathy (using 640 cases and 355022 controls (OR= 30.02, P= 1.90e-04)) under an additive model. Furthermore, we observed an association with cardiomyopathy (using 1974 cases and 365360 controls (OR= 13.36, P= 1.25e-03)) under a recessive model. This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PS4, PM2, PP5) this variant classifies as likely pathogenic.