ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1025G>A (p.Arg342Gln) (rs28935493)

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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 RCV000723455 SCV000110102 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000011490 SCV000695727 pathogenic Fabry disease 2017-02-03 criteria provided, single submitter clinical testing Variant summary: The GLA c.1025G>A (p.Arg342Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 87610 control chromosomes and has been reported in numerous affected individuals in the literature. Alpha-Gal activity was reported as <10% in patients as well as cultured HEK-293 cells, reported in the literature. The variant is located in a CpG dinucleotide, which are known hotspots for mutation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000011490 SCV000839958 pathogenic Fabry disease 2017-10-15 criteria provided, single submitter clinical testing A hemizygous c.1025G>A (p.R342Q) pathogenic variant in the GLA gene was detected in this individual. This variant has been previously reported in patients with Fabry disease (PMID, 11531972, 18424138, 24626659, 2458695). Defects in GLA are the cause of Fabry disease [MIM:301500], an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. Studies characterizing the effect of the c.1025G>A (p.R342Q) on GLA function have shown impaired GLA activity (PMID, 21598360, 23935525). Therefore, this variant is classified as a pathogenic variant in accordance with ACMG guidelines.
Invitae RCV000011490 SCV000936529 pathogenic Fabry disease 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 342 of the GLA protein (p.Arg342Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Fabry disease, and has been shown to segregate with disease in a family (PMID: 8012363, 24626659). ClinVar contains an entry for this variant (Variation ID: 10742). Experimental studies have shown that this missense change abolishes GLA enzymatic activity (PMID: 21598360, 23935525). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011490 SCV000031722 pathogenic Fabry disease 2001-07-01 no assertion criteria provided literature only

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