ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.346+1G>A

dbSNP: rs797044432
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672344 SCV000797441 pathogenic Tay-Sachs disease 2018-01-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000672344 SCV001339061 pathogenic Tay-Sachs disease 2020-03-19 criteria provided, single submitter clinical testing Variant summary: HEXA c.346+1G>A 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. At least one publication reports experimental evidence that this variant affects skipping of exon 2 (Akli_1991). The variant was absent in 251296 control chromosomes (gnomAD). c.346+1G>A has been reported in the literature in individuals (both compound heterozygous and homozygous) affected with Tay-Sachs Disease (Akli_1991, Dastsooz_2018). These data indicate that the variant may be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000672344 SCV004297649 pathogenic Tay-Sachs disease 2023-06-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 556348). This variant is also known as G to A substitution at position 1 of IVS2. . Disruption of this splice site has been observed in individuals with Tay-Sachs disease (PMID: 1837283, 34554397). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
OMIM RCV000672344 SCV000024285 pathogenic Tay-Sachs disease 1992-10-01 no assertion criteria provided literature only
Natera, Inc. RCV000672344 SCV002089755 pathogenic Tay-Sachs disease 2017-03-17 no assertion criteria provided clinical testing

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