ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.571-1G>T (rs185429231)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000689539 SCV000817193 pathogenic Tay-Sachs disease 2019-03-11 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the HEXA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs185429231, ExAC 0.06%). This variant is a common cause of hexosaminidase A deficiency in Japan (PMID: 8484765, 12027830). This variant is also known as Int5-SA(g-1>t) in the literature. Experimental studies have shown that this intronic change leads to the in-frame deletion of exon 6 of the HEXA mRNA (PMID: 8484765). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000689539 SCV000917519 pathogenic Tay-Sachs disease 2018-06-25 criteria provided, single submitter clinical testing Variant summary: HEXA c.571-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant allele was found at a frequency of 1.2e-05 in 246232 control chromosomes (gnomAD). The variant, c.571-1G>T, has been reported in the literature in multiple individuals affected with Tay-Sachs Disease where it was indicated to be one of the major mutations found in the Japanese population (Tanaka_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000689539 SCV001251820 pathogenic Tay-Sachs disease 2020-05-03 criteria provided, single submitter clinical testing

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