ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.460-1G>T (rs764343937)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000586741 SCV000697169 pathogenic Tay-Sachs disease 2016-06-03 criteria provided, single submitter clinical testing Variant summary: The HEXA c.460-1G>T variant involves the alteration of a conserved intronic nucleotide at the splice acceptor site of intron 4. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 3' splicing acceptor site. This variant has been found in two patients with Tay-Sachs disease in homozygous and heterozygous state, repectively. HEX A activity in these patients was extremely low or absent. This variant was also found in 3/96942 control chromosomes at a frequency of 0.0000309, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). In addition, OMIM and HGMD report this variant as pathogenic/disease variant. Taken together, this variant was classified as pathogenic.
Invitae RCV000586741 SCV001418564 pathogenic Tay-Sachs disease 2019-10-25 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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 (rs764343937, ExAC 0.02%). This variant has been observed to be homozygous in an individual affected with Tay-Sachs disease (PMID: 1827945). ClinVar contains an entry for this variant (Variation ID: 496011). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Counsyl RCV000586741 SCV001132223 likely pathogenic Tay-Sachs disease 2014-01-30 no assertion criteria provided clinical testing

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