Submissions for variant NM_000521.4(HEXB):c.558+5G>A

gnomAD frequency: 0.00001  dbSNP: rs892920643

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669675	SCV000794451	uncertain significance	Sandhoff disease	2017-09-26	criteria provided, single submitter	clinical testing
Invitae	RCV000669675	SCV000947101	pathogenic	Sandhoff disease	2023-09-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 23046579). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 554107). This variant has been observed in individual(s) with Sandhoff disease (PMID: 23046579). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency).
Revvity Omics, Revvity	RCV000669675	SCV003834225	likely pathogenic	Sandhoff disease	2022-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000669675	SCV003929048	likely pathogenic	Sandhoff disease	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: HEXB c.558+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: Three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, resulting in the skipping of exon 4 which leads to a premature truncation (Gaignard_2013). The variant was absent in 244516 control chromosomes (gnomAD). c.558+5G>A has been reported in the literature in one individual affected with Sandhoff Disease, who had a pathogenic variant in trans (Gaignard_2013). These data do not allow for an unequivocal conclusion about variant significance. The following publication has been ascertained in the context of this evaluation (PMID: 23046579). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=1)/likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.