Submissions for variant NM_000521.4(HEXB):c.1614-14C>A

gnomAD frequency: 0.00019  dbSNP: rs201448394

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079060	SCV000110929	benign	not specified	2012-08-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000079060	SCV000304649	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000079060	SCV000513237	likely benign	not specified	2017-02-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000673104	SCV000798272	likely benign	Sandhoff disease	2018-03-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000079060	SCV000919511	benign	not specified	2018-12-10	criteria provided, single submitter	clinical testing	Variant summary: HEXB c.1614-14C>A 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. 5/5 computational tools predict no significant impact on normal splicing, which a functional study, Sobek_2012, supports these predictions. The variant allele was found at a frequency of 0.00017 in 277098 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (0.00017 vs 0.0015), allowing no conclusion about variant significance. c.1614-14C>A has been reported in the literature in individuals affected with Sandhoff Disease (Giagnard_2013, Jarnes_2017, Sobek_2012). Although multiple reported affected individuals carried the variant in cis with another pathogenic HEXB variant, in particular, the exon 1-5 deletion, c.-117_669del was reported to be linked with the variant (Sobek_2012). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000673104	SCV001018425	likely benign	Sandhoff disease	2024-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000673104	SCV001315842	likely benign	Sandhoff disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001310507	SCV001500339	likely benign	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000673104	SCV002084957	likely benign	Sandhoff disease	2020-04-03	no assertion criteria provided	clinical testing