ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.884T>G (p.Phe295Cys)

dbSNP: rs1928168711
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Total submissions: 1
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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 RCV001293628 SCV001482259 pathogenic Fabry disease 2021-02-23 criteria provided, single submitter clinical testing Variant summary: GLA c.884T>G (p.Phe295Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183467 control chromosomes. c.884T>G has been reported in the literature in multiple individuals affected with Fabry Disease (Wu_2011, Echevarria_2015, Mauhin_2018). These data indicate that the variant is very likely to be associated with disease. In experimental studies, the variant was consistently reported to have drastically reduced alpha-Gal activity compared to normal: t-cells grown from Fabry disease patients showed 1% alpha-Gal activity, which increased to 29% with the addition of Migalastat (Shin_2008). Similarly, cultured HEK-293 cells showed 4% alpha-Gal activity, which increased to 44% with addition of Migalastat (Wu_2011). However, PBMCs from a patient with Fabry disease, which showed 0% alpha-Gal activity, did not show a meaningful increase in activity with the addition of Migalastat (Wu_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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