ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.805G>A (p.Val269Met) (rs869312427)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589129 SCV000695748 pathogenic Fabry disease 2016-07-04 criteria provided, single submitter clinical testing Variant summary: The GLA c.805G>A (p.Val269Met) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome. Valine-269 is on a loop between the beta 7-strand and alfa 7-helix that surrounds the entrance to the active site (Shabbeer_2006). Multiple functional studies show that this variant severely impairs enzymatic activity and the enzymatic activity is less severe than that of D264Y or D264Y-V269M mutants (Shabbeer_2006, Andreotti_2011, Lukas_2013). This variant is absent in 87124 control chromosomes from ExAC. The variant has been reported in several FAB patients in literature and by a clinical diagnostic center in ClinVar. In an extensive pedigree from Brazil comprising 610 members, 79 had confirmed molecular diagnoses of Fabry disease (V269M) (Pereira_2014). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. On the same codon, other missense variants, namely p.V269A and p.V269G have also been reported in patients with Fabry disease in literature and databases, suggesting that this codon is likely to be a mutational hot-spot. Taken together, this variant is classified as Pathogenic.

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