Submissions for variant NM_000520.6(HEXA):c.986+3A>G

gnomAD frequency: 0.00004  dbSNP: rs200926928

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169296	SCV000220615	likely pathogenic	Tay-Sachs disease	2014-08-21	criteria provided, single submitter	literature only
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000169296	SCV000584096	pathogenic	Tay-Sachs disease	2016-10-13	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000169296	SCV000914693	likely pathogenic	Tay-Sachs disease	2017-09-08	criteria provided, single submitter	clinical testing	The HEXA c.986+3A>G splice region variant has been reported in at least four studies in which it is found in a total of three patients in a compound heterozygous state and in a heterozygous state in one obligate carrier (Richard et al. 1995; Akerman et al. 1997; Giraud et al. 2010; Saunders et al. 2012). One compound heterozygote presented with the late-infantile onset form of Tay-Sachs disease while another compound heterozygote had onset in adulthood. Control data are unavailable for this variant which is reported at a frequency of 0.000025 in the total population from the Exome Aggregation Consortium. In one study, exons 7 to 9 of the c.986+3A>G variant HEXA were amplified and the resulting mRNA product was shown to be lacking exon 8, suggesting this variant affects splicing (Richard et al. 1995). Based on the evidence, the c.986+3A>G variant is classified as likely pathogenic for hexoaminidase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169296	SCV000919505	pathogenic	Tay-Sachs disease	2018-04-09	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.986+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. A publication, Richard_1995, functionally assessed the variant and found it to cause exon 8 to be deleted, which is located in the Glycoside hydrolase family 20, catalytic domain (via InterPro). The variant was observed with an allele frequency of 8.1e-06 in 246182 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (8.1e-06 vs 0.0014), allowing no conclusion about variant significance. The variant, c.986+3A>G, has been reported in the literature in individuals affected with Tay-Sachs Disease. These data indicate that the variant is likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000169296	SCV000937827	pathogenic	Tay-Sachs disease	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs200926928, gnomAD 0.01%). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 7551830, 23035047, 24518553). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188929). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8 and introduces a premature termination codon (PMID: 7551830). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003441767	SCV004168354	likely pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant a damaging effect on splicing of HEXA mRNA (Richard et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 9150157, 24518553, 20100466, 29790872, 7551830, 23035047)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169296	SCV004847334	pathogenic	Tay-Sachs disease	2023-09-12	criteria provided, single submitter	clinical testing	The c.1019+3A>G variant in HEXA (also reported as c.986+3A>G in the literature) has been reported in the compound heterozygous state in at least 3 individuals with Tay-Sachs disease and in the heterozygous state in 1 individual where a second HEXA allele was not identified (Richard 1995 PMID: 7551830, Giraud 2010 PMID: 20100466, Saunders 2012 PMID: 23035047, Jamali 2014 PMID: 24518553). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID: 188929) and been identified in 0.007% (5/68032) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is located in the 3' splice region. Computational tools predict a splicing impact, and functional studies confirm skipping of exon 8 leading to a premature stop codon which is predicted to result in an abnormal or absent protein (Richard 1995 PMID: 7551830). Biallelic loss of function of the HEXA gene is an established disease mechanism in autosomal recessive Tay-Sachs disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Tay-Sachs disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting.
Natera, Inc.	RCV000169296	SCV002085687	pathogenic	Tay-Sachs disease	2017-03-16	no assertion criteria provided	clinical testing