ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1495C>T (p.Arg499Cys)

gnomAD frequency: 0.00001  dbSNP: rs121907966
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169417 SCV000220823 likely pathogenic Tay-Sachs disease 2014-10-21 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169417 SCV000697165 pathogenic Tay-Sachs disease 2016-09-29 criteria provided, single submitter clinical testing Variant summary: The HEXA c.1495C>T (p.Arg499Cys) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from 121370 control chromosomes, but has been reported in numerous infantile and late-onset Tay-Sachs patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Laboratory Services,Illumina RCV000169417 SCV001451590 pathogenic Tay-Sachs disease 2019-01-15 criteria provided, single submitter clinical testing The HEXA c.1495C>T (p.Arg499Cys) variant is a well-described missense variant. Across a selection of the available literature, it has been reported in five unrelated individuals with hexosaminidase A deficiency, including in a homozygous state in one infantile case and in a compound heterozygous state in three infantile/late infantile cases and one adult-onset case (Mules et al. 1992; Akli et al. 1993; Tanaka et al. 2003; Maegawa et al. 2006; Gort et al. 2012). The p.Arg499Cys variant is reported at a frequency of 0.000029 in the Latino population of the Genome Aggregation Database, but this frequency is based on one allele only in a region of good sequencing coverage. The variant is therefore presumed to be rare. Functional studies of the variant have not been conducted, but the variant affects a CpG dinucleotide, and another missense change at the same position has also been shown to be pathogenic. Based on the collective evidence, the p.Arg499Cys variant is classified as pathogenic for hexosaminidase A deficiency.
Invitae RCV000169417 SCV002239437 pathogenic Tay-Sachs disease 2021-10-14 criteria provided, single submitter clinical testing
OMIM RCV000004121 SCV000024287 pathogenic Gm2-gangliosidosis, adult-onset 2003-01-01 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000169417 SCV000494229 pathogenic Tay-Sachs disease 2014-11-14 no assertion criteria provided research
Natera, Inc. RCV000169417 SCV002085656 pathogenic Tay-Sachs disease 2017-03-16 no assertion criteria provided clinical testing

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