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

gnomAD frequency: 0.00002  dbSNP: rs185429231

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689539	SCV000817193	pathogenic	Tay-Sachs disease	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the HEXA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs185429231, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with hexosaminidase A deficiency (PMID: 8484765, 12027830). It has also been observed to segregate with disease in related individuals. This variant is also known as Int5-SA(g-1>t). ClinVar contains an entry for this variant (Variation ID: 569012). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 8484765). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Revvity Omics, Revvity	RCV000689539	SCV004236146	pathogenic	Tay-Sachs disease	2023-05-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000689539	SCV002086295	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing