Submissions for variant NM_000520.6(HEXA):c.1123del (p.Glu375fs)

dbSNP: rs766138785

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169594	SCV000221104	likely pathogenic	Tay-Sachs disease	2015-01-30	criteria provided, single submitter	literature only
Invitae	RCV000169594	SCV001204958	pathogenic	Tay-Sachs disease	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu375Argfs*7) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 16088929, 31076878). ClinVar contains an entry for this variant (Variation ID: 189166). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169594	SCV001362846	pathogenic	Tay-Sachs disease	2019-11-25	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1123delG (p.Glu375ArgfsX7) 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 8.1e-06 in 246288 control chromosomes. c.1123delG has been reported in the literature in individuals affected with Tay-Sachs Disease (example, Montalvo_2005, Jamrozik_2013, Jahnova_2019). These data indicate that the variant is likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained in the context of this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169594	SCV001440216	likely pathogenic	Tay-Sachs disease	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268863	SCV001448073	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000169594	SCV002580325	pathogenic	Tay-Sachs disease	2022-02-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001268863	SCV004219901	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the HEXA mRNA and causes the premature termination of HEXA protein synthesis. In the published literature, the variant has been reported as compound heterozygous with other pathogenic variants in individuals with Tay-Sachs Disease (PMIDs: 16088929 (2005), 23820084 (2013), and 31076878 (2019)). Based on the available information, this variant is classified as pathogenic.
Natera, Inc.	RCV000169594	SCV002085680	pathogenic	Tay-Sachs disease	2017-03-16	no assertion criteria provided	clinical testing