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

dbSNP: rs988192535

Total submissions: 6

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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666873	SCV000939243	pathogenic	Tay-Sachs disease	2025-01-19	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. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. ClinVar contains an entry for this variant (Variation ID: 551737). 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.
GeneDx	RCV002466558	SCV002762601	pathogenic	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 1833974, 9150157, 8490625, 33811753)
Natera, Inc.	RCV000666873	SCV002085678	pathogenic	Tay-Sachs disease	2021-08-26	no assertion criteria provided	clinical testing