ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1527-6T>C (rs199914308)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724516 SCV000226036 uncertain significance not provided 2015-01-02 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000246203 SCV000304641 likely benign not specified criteria provided, single submitter clinical testing
Invitae RCV000462401 SCV000557161 likely benign Tay-Sachs disease 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000462401 SCV000793128 likely benign Tay-Sachs disease 2017-07-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2020-08-07 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, 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 neutral polymorphism (Myerowitz_1997). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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