Submissions for variant NM_000520.6(HEXA):c.1528C>T (p.Arg510Ter)

gnomAD frequency: 0.00001  dbSNP: rs786204585

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421085	SCV000521178	pathogenic	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 20 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27896118, 21567908, 22789865, 33547378)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169328	SCV000814792	pathogenic	Tay-Sachs disease	2023-09-06	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188954). This premature translational stop signal has been observed in individual(s) with hexosaminidase A deficiency (PMID: 21567908, 22789865, 27896118). This sequence change creates a premature translational stop signal (p.Arg510*) in the HEXA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the HEXA protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169328	SCV000919503	pathogenic	Tay-Sachs disease	2018-04-02	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1528C>T (p.Arg510X) 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. The variant was absent in 120496 control chromosomes (ExAC and publication controls). The variant, c.1528C>T, has been reported in the literature in multiple individuals affected with Tay-Sachs Disease. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000169328	SCV002030166	pathogenic	Tay-Sachs disease	2021-09-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Myriad Genetics, Inc.	RCV000169328	SCV002060198	pathogenic	Tay-Sachs disease	2021-11-10	criteria provided, single submitter	clinical testing	NM_000520.4(HEXA):c.1528C>T(R510*) is a nonsense variant classified as pathogenic in the context of hexosaminidase A deficiency. R510* has been observed in cases with relevant disease (PMID: 33547378, 27896118, 21567908). Functional assessments of this variant are not available in the literature. R510* has not been observed in population frequency databases. In summary, NM_000520.4(HEXA):c.1528C>T(R510*) is a nonsense variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000169328	SCV003835069	pathogenic	Tay-Sachs disease	2021-01-06	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000169328	SCV000494230	pathogenic	Tay-Sachs disease	2010-08-26	no assertion criteria provided	research
Natera, Inc.	RCV000169328	SCV002085648	pathogenic	Tay-Sachs disease	2017-12-09	no assertion criteria provided	clinical testing