ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1168C>T (p.Gln390Ter) (rs988192535)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666873 SCV000791237 likely pathogenic Tay-Sachs disease 2017-05-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000666873 SCV000917515 pathogenic Tay-Sachs disease 2018-05-03 criteria provided, single submitter clinical testing Variant summary: HEXA c.1168C>T (p.Gln390X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1274_1277dupTATC (p.Tyr427fsX5) and c.1528C>T (p.Arg510X)). The variant, c.1168C>T, has been reported in the literature in an individual affected with Tay-Sachs Disease presenting with no hexosaminidase A activity (Jin_2004). This data indicates that the variant may be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000666873 SCV000939243 pathogenic Tay-Sachs disease 2018-08-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln390*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed as heterozygous in an unaffected individual (PMID: 9150157). Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002233 SCV001160108 pathogenic not specified 2018-11-15 criteria provided, single submitter clinical testing The HEXA c.1168C>T; p.Gln390Ter variant is reported in the literature in an obligate carrier of Tay-Sachs disease (Akerman 1997) and is reported as likely pathogenic by a single laboratory in ClinVar (Variation ID: 551737). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Further, numerous truncating variants downstream of this variant have been observed in individuals with Tay-Sachs disease and are considered pathogenic (Montalvo 2005, Zampieri 2012). Based on available information, the p.Gln390Ter variant is considered to be pathogenic. References: Akerman BR et al. Novel mutations and DNA-based screening in non-Jewish carriers of Tay-Sachs disease. Am J Hum Genet. 1997 May;60(5):1099-106. Montalvo AL et al. Molecular analysis of the HEXA gene in Italian patients with infantile and late onset Tay-Sachs disease: detection of fourteen novel alleles. Hum Mutat. 2005 Sep;26(3):282. Zampieri S et al. Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. Gene. 2012 May 15;499(2):262-5.

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