ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.713G>A (p.Ser238Asn) (rs730880450)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000157899 SCV000281230 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000157899 SCV000207830 pathogenic not provided 2012-12-10 criteria provided, single submitter clinical testing The Ser238Asn mutation in the GLA gene has been reported in two unrelated males with late onset HCM and low plasma galactosidase A activity (Monserrat L et al., 2007). Mutations in nearby residues (Trp236Arg, Trp236Cys, Trp236Leu, Ile239Thr, Ile242Thr) have been reported in association with Fabry disease, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ser238Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000781420 SCV000919438 pathogenic Fabry disease 2018-04-30 criteria provided, single submitter clinical testing Variant summary: GLA c.713G>A (p.Ser238Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 200565 control chromosomes. c.713G>A has been reported in the literature in individuals with phenotypes ranging from classic Fabry disease (Vieitez_GLA_OJRD_2018) to seemingly isolated GLA-HCM (Monserrat_2007), to late-onset Fabry disease, which may be related to skewed X-inactivation with predominant expression of the wild-type GLA allele (Echevarria_2015). These data indicate that the variant is likely to be associated with disease. In vitro enzyme activity was shown to be 36% of wild-type (Lukas_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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