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

dbSNP: rs147324677

Total submissions: 3

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670361	SCV001589169	pathogenic	Tay-Sachs disease	2020-08-07	criteria provided, single submitter	clinical testing	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). 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). 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.
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.