Submissions for variant NM_000521.4(HEXB):c.1082+5G>A

gnomAD frequency: 0.00004  dbSNP: rs5030731

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000308357	SCV000458186	likely pathogenic	Sandhoff disease	2016-08-16	criteria provided, single submitter	clinical testing	The HEXB c.1082+5G>A splice region variant has been reported in two individuals with Sandhoff disease, including one homozygote and one compound heterozygote (Zampieri et al. 2012; Chiricozzi et al. 2013). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. In silico analysis and in vitro functional studies demonstrated that the c.1082+5G>A variant produces a shorter transcript that lacks exon 8, and this leads to a frameshift and the generation of a premature stop codon (Zampieri et al. 2012). Based on the evidence, the c.1082+5G>A variant is classified as likely pathogenic for Sandhoff disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000308357	SCV000629382	pathogenic	Sandhoff disease	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. It affects a nucleotide within the consensus splice site. 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 variant has been observed in individual(s) with Sandhoff disease (PMID: 22789865, 22848519, 30548430). ClinVar contains an entry for this variant (Variation ID: 354135). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22848519). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000308357	SCV001426569	pathogenic	Sandhoff disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000308357	SCV002548066	pathogenic	Sandhoff disease	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: HEXB c.1082+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and one predicts the variant weakens a 5' donor site. This has been experimentally validated via a minigene splicing assay, which reported the variant caused loss of 178 nucleotides in exon 8, resulting in a frameshift (p.G301_W361delfsX10, Zampieri_2012). The variant allele was found at a frequency of 4e-06 in 250056 control chromosomes (gnomAD). c.1082+5G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Sandhoff Disease (Zampieri_2012, Gort_2012, Gheldof_2019, Bertoli-Avella_2021). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters have assessed the variant since 2014: two classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000308357	SCV004238236	likely pathogenic	Sandhoff disease	2023-06-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000308357	SCV000795893	likely pathogenic	Sandhoff disease	2018-11-07	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000308357	SCV002084944	pathogenic	Sandhoff disease	2020-09-04	no assertion criteria provided	clinical testing