ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1421+1G>C (rs147324677)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255737 SCV000322422 pathogenic not provided 2018-03-19 criteria provided, single submitter clinical testing The c.1421+1 G>C splice site variant in the HEXA gene has been reported previously in association with infantile-onset Tay-Sachs disease (Ohno et al. 1988). The c.1421+1 G>C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Analysis of c.1421+1 G>C cDNA clones found that this variant results in abnormal gene splicing (Ohno et al. 1988). In summary, we interpret c.1421+1 G>C to be pathogenic.
Myriad Women's Health, Inc. RCV000004094 SCV000678055 pathogenic Tay-Sachs disease 2015-10-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004094 SCV000697163 pathogenic Tay-Sachs disease 2016-01-19 criteria provided, single submitter clinical testing Variant summary: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict this variant to have a major effect on splicing pattern. These predictions were confirmed by Ohno et al (1988) who showed that this variants leads to exon12 skipping. This variant has been reported in the literature in multiple affected individuals presented with classic Tay-Sachs disease. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 15% of cases in this ethnic group (Montavlo, 2005). The variant is present in the broad control population dataset of ExAC at a low frequency exclusively in European cohort (0.0165%), which does not exceed the maximum frequency for a pathogenic variant in HEXA gene (0.14%). Taking together, the variant was classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000004094 SCV000894056 pathogenic Tay-Sachs disease 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000004094 SCV000931129 pathogenic Tay-Sachs disease 2019-12-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the HEXA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs147324677, ExAC 0.02%). This variant has been reported as homozygous or in combination with another HEXA variant in individuals affected with Tay-Sachs disease (PMID: 3375249, 3362213, 2973464, 2837213, 9222766). This variant is a common cause of Tay-Sachs in the Ashkenazi Jewish population (PMID: 16088929). ClinVar contains an entry for this variant (Variation ID: 3890). This variant is also known as IVS12+1G>C. Experimental studies have shown that this splice site change disrupts splicing (PMID: 2973464, 2837213). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000004094 SCV001194175 pathogenic Tay-Sachs disease 2019-12-19 criteria provided, single submitter clinical testing NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 3375249, 2837213, 3362213, 9222766 and 2973464. Classification of NM_000520.4(HEXA):c.1421+1G>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000004094 SCV000024260 pathogenic Tay-Sachs disease 1997-01-01 no assertion criteria provided literature only

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