ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.806-7G>A (rs770932296)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000191092 SCV000245490 pathogenic Tay-Sachs disease 2014-07-02 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [c.1073+1G>A] in a 25-year-old female with motor delay, hypotonia, scoliosis, progressive weakness, mild ankle contractures, mildly diminished sensation, gait abnormalities, sister possibly similarly symptomatic (not tested). Variant pathogenic in recessive state; heterozygotes are carriers.
Counsyl RCV000191092 SCV000800502 uncertain significance Tay-Sachs disease 2017-03-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780338 SCV000917520 uncertain significance not specified 2018-10-01 criteria provided, single submitter clinical testing Variant summary: HEXA c.806-7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. At least one publication reports experimental evidence that this variant affects mRNA splicing (Fernandes_1997). The variant allele was found at a frequency of 2.2e-05 in 276116 control chromosomes. c.806-7G>A has been reported in the literature in one compound heterozygous individual affected with chronic Tay-Sachs Disease (Fernandes_1997). This publication also reported experimental evidence evaluating an impact on splicing and enzyme activity and showed the variant results in <10% of normal enzyme activity likely due to a significant decrease in the amount of WT transcript produced. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance, though two earlier submissions classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000191092 SCV000932244 pathogenic Tay-Sachs disease 2020-08-30 criteria provided, single submitter clinical testing This sequence change falls in intron 7 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. This variant is present in population databases (rs770932296, ExAC 0.005%). This variant has been observed in individual(s) with clinical features of Tay-Sachs disease (PMID: 9272736, Invitae, external communication). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 209160). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285271 SCV001471674 likely pathogenic none provided 2019-08-30 criteria provided, single submitter clinical testing The HEXA c.806-7G>A variant (rs770932296) is reported in the literature in an individual affected with chronic GM2-gangliosidosis that also carried a second pathogenic variant (Fernandes 1997). This variant is found on only seven chromosomes (7/281768 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Indeed, analyses of mRNAs from an individual carrying this variant indicates a >80% decrease in mRNA levels and skipping of exon 8 (Fernandes 1997). Based on available information, this variant is considered to be likely pathogenic. References: Fernandes MJ et al. A chronic GM2 gangliosidosis variant with a HEXA splicing defect: quantitation of HEXA mRNAs in normal and mutant fibroblasts. Eur J Hum Genet. 1997 May-Jun;5(3):129-36.
GeneDx RCV001582679 SCV001812599 pathogenic not provided 2019-11-29 criteria provided, single submitter clinical testing Introduces a new splice acceptor site upstream of the normal intron 7 splice acceptor site and leads to a more than 80% reduction of steady-state HEXA mRNA levels (Fernandes et al., 1997); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17001642, 9272736, 26633545)
OMIM RCV000004146 SCV000024312 pathogenic Gm2-gangliosidosis, chronic 1992-12-01 no assertion criteria provided literature only

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