Submissions for variant NM_000520.6(HEXA):c.1499del (p.Leu500fs)

dbSNP: rs1567295184

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000758204	SCV000917516	likely pathogenic	Tay-Sachs disease	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: Variant summary: HEXA c.1499delT (p.Leu500CysfsX9) 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. The variant allele was found at a frequency of 4e-06 in 251566 control chromosomes. c.1499delT has been reported in the literature as a carrier genotype in at-least one obligate carrier parent of an infant reportedly affected with Tay-Sachs disease (example, McGinniss_2002) and as a compound heterozygous genotype in at-least one young adult man with late-onset Tay-Sachs disease (example, Barritt_2017). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 28% and 52% of normal HEX A enzyme activity in the serum and WBC respectively of an obligate carrier (McGinniss_2002). Another study reports 15% of normal HEX A enzyme activity in WBC of an affected compound heterozygote individual (Barritt_2017). Three clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000758204	SCV002232341	pathogenic	Tay-Sachs disease	2023-09-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu500Cysfs*9) in the HEXA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the HEXA protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with late-onset Tay–Sachs disease (PMID: 28739864). ClinVar contains an entry for this variant (Variation ID: 619222). This variant disrupts a region of the HEXA protein in which other variant(s) (p.Leu517Profs*7) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000758204	SCV002790987	likely pathogenic	Tay-Sachs disease	2021-08-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003983198	SCV004800505	pathogenic	HEXA-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The HEXA c.1499delT variant is predicted to result in a frameshift and premature protein termination (p.Leu500Cysfs*9). This variant has been reported, along with the HEXA c.805GA (p.Gly269Ser) variant, in an individual with adult onset Tay-Sachs disease (Barritt et al. 2017. PubMed ID: 28739864). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in HEXA are expected to be pathogenic. This variant is interpreted as pathogenic.
Sema4, Sema4	RCV000758204	SCV000886516	pathogenic	Tay-Sachs disease	2018-10-26	no assertion criteria provided	clinical testing