Submissions for variant NM_000520.6(HEXA):c.1527-6T>C

gnomAD frequency: 0.00087  dbSNP: rs199914308

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724516	SCV000226036	uncertain significance	not provided	2015-01-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000246203	SCV000304641	likely benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000462401	SCV000557161	likely benign	Tay-Sachs disease	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000462401	SCV000793128	likely benign	Tay-Sachs disease	2017-07-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000462401	SCV001275076	uncertain significance	Tay-Sachs disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000246203	SCV001431934	likely benign	not specified	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.1527-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 251334 control chromosomes including 3 homozygotes (gnomAD). The variant occurs predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. This frequency is slightly lower than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (0.0012 vs 0.0014), suggesting this variant may be benign. c.1527-6T>C has been reported in the literature in individuals affected with Tay-Sachs Disease and classified as a neutral polymorphism (Myerowitz_1997). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: two classified it as uncertain significance, four as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000724516	SCV001881577	likely benign	not provided	2020-11-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 9090523)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724516	SCV002046466	likely benign	not provided	2020-12-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724516	SCV002049725	benign	not provided	2021-09-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000462401	SCV002085649	benign	Tay-Sachs disease	2017-08-10	no assertion criteria provided	clinical testing