Submissions for variant NM_000520.6(HEXA):c.929_930del (p.Ser310fs)

dbSNP: rs751248523

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mayo Clinic Laboratories, Mayo Clinic	RCV000681660	SCV000809107	pathogenic	Tay-Sachs disease	2018-06-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000681660	SCV001362844	pathogenic	Tay-Sachs disease	2019-01-22	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.929_930delCT (p.Ser310CysfsX13) 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. p.Gln390X, p.Tyr427fsX5, p.Arg510X). The variant allele was found at a frequency of 5.3e-05 in 246224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.3e-05 vs 0.0014), allowing no conclusion about variant significance. c.929_930delCT has been reported in the literature in individuals affected with Tay-Sachs Disease (Fernandes_1992, Nestrasil_2018, Utz_2015, Utz_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
Invitae	RCV000681660	SCV001588140	pathogenic	Tay-Sachs disease	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser310Cysfs*13) 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 present in population databases (rs751248523, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 1302612). ClinVar contains an entry for this variant (Variation ID: 562219). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001566339	SCV001789841	pathogenic	not provided	2019-10-28	criteria provided, single submitter	clinical testing	Frameshift 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 1302612, 25557439)
GeneID Lab - Advanced Molecular Diagnostics	RCV000681660	SCV002011812	pathogenic	Tay-Sachs disease	2019-07-29	criteria provided, single submitter	clinical testing	This variant causes a frameshift; starting at Serine 310, changes this amino acid to a Cysteine residue and creates a premature stop codon in the new reading frame, denoted p.Ser310Cysfs*13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This finding is present in the gnomAD exomes database at an allele frequency of 0.0000517. This variant has been described in patiens diagnosed with Tay-Sachs disease (PMID: 1302612, 29352662). Based on these findings we consider this subtitution as "Pathogenic".
Fulgent Genetics, Fulgent Genetics	RCV000681660	SCV002813822	pathogenic	Tay-Sachs disease	2021-11-05	criteria provided, single submitter	clinical testing
OMIM	RCV000681660	SCV000024298	affects	Tay-Sachs disease	2021-09-09	no assertion criteria provided	literature only
Natera, Inc.	RCV000681660	SCV002085689	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing