ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1421+1G>T

dbSNP: rs147324677
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670361 SCV000795203 likely pathogenic Tay-Sachs disease 2017-11-06 criteria provided, single submitter clinical testing
Invitae RCV000670361 SCV001589169 pathogenic Tay-Sachs disease 2020-08-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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). 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. Disruption of this splice site has been observed to be homozygous in an individual affected with Tay-Sachs disease (PMID: 9222766) and is a common cause of Tay-Sachs in the Ashkenazi Jewish population (PMID: 16088929, 30506202). This sequence change affects a donor splice site in intron 12 of the HEXA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670361 SCV004039523 likely pathogenic Tay-Sachs disease 2023-08-15 criteria provided, single submitter clinical testing Variant summary: HEXA c.1421+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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250594 control chromosomes. To our knowledge, no occurrence of c.1421+1G>T in individuals affected with Tay-Sachs Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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