ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1496G>A (p.Arg499His) (rs121907956)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210735 SCV000263008 uncertain significance Inborn genetic diseases 2017-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000520531 SCV000331828 pathogenic not provided 2015-11-06 criteria provided, single submitter clinical testing
GeneDx RCV000520531 SCV000617692 pathogenic not provided 2017-11-02 criteria provided, single submitter clinical testing The R499H pathogenic variant in the HEXA gene has been reported previously in association with juvenile Tay-Sachs disease as a single variant in an affected individual, as well as in trans with a second HEXA variant (Paw et al., 1990; Triggs-Raine et al., 1991). A structural analysis of the alpha-subunit of beta-hexosaminidase indicates that the R499H variant results in a retention of the Hex­ alpha-subunit in the ER and posterior degradation along with a lower value of the solven­t-accessible surface area (Ohno et al., 2008). Though not observed in the homozygous state, the R499H variant is observed in 10/30,780 (0.03%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). The R499H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R499H as a pathogenic variant.
Invitae RCV000338961 SCV000820054 pathogenic Tay-Sachs disease 2018-06-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 499 of the HEXA protein (p.Arg499His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs121907956, ExAC 0.04%). This variant has been reported in combination with other pathogenic HEXA variants in several individuals affected with Tay-Sachs disease (PMID: 14577003, 17237499, 2144098). ClinVar contains an entry for this variant (Variation ID: 3899). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000338961 SCV000917512 pathogenic Tay-Sachs disease 2018-02-12 criteria provided, single submitter clinical testing Variant summary: HEXA c.1496G>A (p.Arg499His) 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, c.1496G>A, was observed with an allele frequency of 5.7e-05 in 246362 control chromosomes (gnomAD and publication controls). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.7e-05 vs 0.0014), allowing no conclusion about variant significance. The variant, c.1496G>A, has been reported in the literature in multiple compound heterozygote individuals affected with Tay-Sachs Disease, while some present with a subacute phenotype or late-onset (adult and juvenile). Multiple clinical diagnostic laboratories via ClinVar submissions (evaluations performed after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004105 SCV000024271 pathogenic Gm2-gangliosidosis, juvenile 2003-01-01 no assertion criteria provided literature only
Counsyl RCV000338961 SCV001132415 pathogenic Tay-Sachs disease 2018-06-17 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.