Submissions for variant NM_000520.6(HEXA):c.805+1G>C

gnomAD frequency: 0.00001  dbSNP: rs121907980

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000416460	SCV000953477	pathogenic	Tay-Sachs disease	2024-03-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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. Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 7827134, 22723944). ClinVar contains an entry for this variant (Variation ID: 375358). 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	RCV000416460	SCV001431883	pathogenic	Tay-Sachs disease	2020-08-03	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.805+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence that this variant affects mRNA splicing, and demonstrated the lack of exon 7 in patient derived mRNA (Ribeiro_1995). The variant allele was found at a frequency of 4e-06 in 251436 control chromosomes (gnomAD). c.805+1G>C has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Tay-Sachs Disease (e.g. Ribeiro_1995, Rozenberg_2004). These data indicate that the variant is very likely to be associated with disease. One of these publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of enzyme activity in leucocytes derived from a homozygous patient (Ribeiro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000416460	SCV002318370	pathogenic	Tay-Sachs disease		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000416460	SCV002811125	pathogenic	Tay-Sachs disease	2021-08-11	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000416460	SCV003807471	pathogenic	Tay-Sachs disease	2022-05-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PS4 supporting, PM2 moderated, PM3 supporting
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000416460	SCV000494218	pathogenic	Tay-Sachs disease	2011-08-11	no assertion criteria provided	research
Natera, Inc.	RCV000416460	SCV002086282	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing