ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.754C>T (p.Arg252Cys) (rs566580738)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000625807 SCV000746363 likely pathogenic Tay-Sachs disease 2017-12-03 criteria provided, single submitter clinical testing
Counsyl RCV000625807 SCV000799553 uncertain significance Tay-Sachs disease 2018-04-25 criteria provided, single submitter clinical testing
Invitae RCV000625807 SCV000833988 likely pathogenic Tay-Sachs disease 2018-03-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 252 of the HEXA protein (p.Arg252Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs566580738, ExAC 0.01%). This variant has been reported in combination with a pathogenic variant in HEXA in an individual affected with a HEXA-related disease (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Other missense substitutions at this codon (p.Arg252Leu and p.Arg252His) have been reported in individuals affected with hexosaminidase A deficiency (PMID: 14566483, 8730294). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, RCV000625807 SCV001244952 uncertain significance Tay-Sachs disease no assertion criteria provided clinical testing

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