ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.1244T>C (p.Leu415Pro)

dbSNP: rs112341092
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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 RCV000587942 SCV000695733 pathogenic Fabry disease 2020-09-03 criteria provided, single submitter clinical testing Variant summary: GLA c.1244T>C (p.Leu415Pro) 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 183414 control chromosomes (gnomAD). c.1244T>C has been reported in the literature in multiple individuals and families affected with classic Fabry Disease (e.g. Larralde_2004, Shin_2008, Wu_2011, Germain_2012, Thurberg_2012, Wilcox_2012, Rozenfeld_2015, Thurberg_2017, Sakuraba_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (e.g. Larralde_2004, Shin_2008, Wu_2011, Germain_2012, Lukas_2013, Lukas_2020). No other 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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