ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.508C>T (p.Arg170Trp) (rs121907972)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Myriad Women's Health, Inc. RCV000004131 SCV001193877 likely pathogenic Tay-Sachs disease 2019-12-20 criteria provided, single submitter clinical testing NM_000520.4(HEXA):c.508C>T(R170W) is classified as likely pathogenic in the context of hexosaminidase A deficiency and and is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 10083731, 8490625, 9169471, 16088929, 22723944, 1302612, 24940364 and 14577003. Classification of NM_000520.4(HEXA):c.508C>T(R170W) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000004131 SCV001225428 pathogenic Tay-Sachs disease 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 170 of the HEXA protein (p.Arg170Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121907972, ExAC 0.009%). This variant has been reported as homozygous or in combination with other HEXA variants in individuals affected with Tay-Sachs disease (PMID: 1302612, 16088929, 22723944, 8490625). ClinVar contains an entry for this variant (Variation ID: 3925). Experimental studies have shown that this missense change interferes with the structure of the HEXA protein and impairs enzyme activity (PMID: 9169471). A different missense substitution at this codon (p.Arg179Gln) has been determined to be pathogenic (PMID: 16088929, 8490625, 24518553, Invitae). This suggests that the arginine residue is critical for HEXA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000004131 SCV001362841 pathogenic Tay-Sachs disease 2019-01-14 criteria provided, single submitter clinical testing Variant summary: HEXA c.508C>T (p.Arg170Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276962 control chromosomes (gnomAD). c.508C>T has been reported in the literature in multiple individuals affected with Tay-Sachs Disease (Mistri_2012, Montalvo_2005, Tanaka_1999, Poenaru_1994, Akli_1993, Fernandes_1992). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact of the variant on protein function demonstrated HexA enzyme activity of 1.03% (expressed as percentage of total Hex activity). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000004131 SCV000024297 pathogenic Tay-Sachs disease 1997-05-01 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000004131 SCV000494208 pathogenic Tay-Sachs disease 2010-09-07 no assertion criteria provided research

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