Submissions for variant NM_000520.6(HEXA):c.1330+1G>A

dbSNP: rs767041069

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410148	SCV000487086	pathogenic	Tay-Sachs disease	2016-10-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000438026	SCV000516070	pathogenic	not provided	2019-05-06	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16088929, 22441121)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410148	SCV001362842	pathogenic	Tay-Sachs disease	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1330+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: Three predict that the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250950 control chromosomes. c.1330+1G>A has been reported in the literature in individuals affected with Tay-Sachs Disease and Juvenile GM2 gangliosidosis (e.g. Montalvo_2005, Maegawa_2006, Zampieri_2012). Patient cells with the variant were shown to have reduced levels of HEXA enzyme activity (e.g. Maegawa_2006). These data indicate that the variant is likely to be associated with disease. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000410148	SCV001589170	pathogenic	Tay-Sachs disease	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 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). This variant is present in population databases (rs767041069, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 16088929, 22441121). ClinVar contains an entry for this variant (Variation ID: 371490). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000410148	SCV004046345	pathogenic	Tay-Sachs disease		criteria provided, single submitter	clinical testing	This variant affects the canonical splice donor site of intron 11 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous or homozygous change in patients with infantile Tay-Sachs disease, Tay-Sachs disease, and late onset Tay-Sachs disease (PMID:16088929, 22441121). The c.1330+1G>A variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/250950) and is absent in the homozygous state, thus it is presumed to be rare. Based on the available evidence, the c.1330+1G>A variant is classified as Pathogenic.
Natera, Inc.	RCV000410148	SCV002085668	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing