ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.782G>T (p.Gly261Val) (rs869312401)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780301 SCV000917463 pathogenic Fabry disease 2018-12-28 criteria provided, single submitter clinical testing Variant summary: GLA c.782G>T (p.Gly261Val) results in a non-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 178774 control chromosomes (gnomAD). c.782G>T has been reported in the literature in multiple individuals affected with Fabry Disease and hypertrophic cardiomyopathy (Wu_2018, Koulousios_2017, Walsh_2017, Alfadhel_2016, Lukas_2013). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function showed that the variant resulted in an in vitro enzyme activity which was <10% of the wild-type and exhibited lyso-Gb3 levels were above the pathological cut-off (Lukas_2013). Based on the evidence outlined above, the variant was classified as pathogenic.
CeMIA RCV000780301 SCV001571672 likely pathogenic Fabry disease criteria provided, single submitter clinical testing The c.782G>T (p.Gly261Val ) variant, located in exon 5 of the GLA gene, has been previously reported in association with Fabry didease in the literature (PMID: 23935525, 27532257, 27629047, 28988177, 29491734). The variant was identified in four members (1 hemizygous male, 3 heterozygous females) of a family, in which only two (1 male, 1 female) were affected with Fabry disease. Bioinformatic analysis by PolyPhen2 algorithm predicted this mutation as probably damaging. It was not detected amongst the 31360 individuals of the Genome Aggregation Database (gnomAD), indicating that it is not a common variant. Missense variants in the same residue have been previously reported in association with Fabry disease (PMID: 9105656, 15712228). Taking all the above into account and according to ACMG Guidelines (Criteria: PM1, PM2, PM5, PP2, PP3, PP4, PP5) the variant is considered likely pathogenic.

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