ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.986+3A>G (rs200926928)

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Total submissions: 5
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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 Clinical Services Laboratory,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.
Integrated Genetics/Laboratory Corporation of America 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 2018-09-19 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs200926928, ExAC 0.02%). This variant has been observed in a patient with Tay-Sachs disease (PMID: 7551830) and on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Tay-Sachs disease (PMID: 23035047). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant was also identified in a individual with Tay-Sachs disease in whom a second variant was not identified (PMID: 24518553). ClinVar contains an entry for this variant (Variation ID: 188929). Experimental studies have shown that this splice site variant leads to the skipping of exon 8 (PMID: 7551830). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. For these reasons, this variant has been classified as Pathogenic.

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