Submissions for variant NM_000521.4(HEXB):c.1509-26G>A

dbSNP: rs201580118

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000633008	SCV000754219	pathogenic	Sandhoff disease	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 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 likely results in the gain of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201580118, gnomAD 0.01%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 2522450, 17015493, 22789865, 24915922; Invitae). ClinVar contains an entry for this variant (Variation ID: 527971). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 2522450). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000633008	SCV000789239	likely pathogenic	Sandhoff disease	2017-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000633008	SCV000919510	pathogenic	Sandhoff disease	2018-11-12	criteria provided, single submitter	clinical testing	Variant summary: HEXB c.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Nakano_1989). The variant allele was found at a frequency of 4.9e-05 in 245836 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (4.9e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.1509-26G>A, has been reported in the literature in multiple individuals affected with Sandhoff Disease, homozygotes and compound heterozygotes (Delnooz_2009, Gort_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Delnooz_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000633008	SCV002579770	likely pathogenic	Sandhoff disease	2022-08-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000633008	SCV002810292	pathogenic	Sandhoff disease	2022-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002529814	SCV003689621	pathogenic	Inborn genetic diseases	2021-08-09	criteria provided, single submitter	clinical testing	The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (12/250940) total alleles studied. The highest observed frequency was 0.01% (12/113452) of European (non-Finnish) alleles. This alteration has been reported in association with Sandhoff disease in homozygotes and in heterozygotes with an additional HEXB variant (Maegawa, 2006; Delnooz, 2010; Gort, 2012; Zhang 2016). Experimental evidence suggests this alteration has an impact on splicing resulting in an in-frame insertion of 24 nucleotides and 8 amino acids (Nakano, 1989). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV003153772	SCV003842519	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-26; This variant is associated with the following publications: (PMID: 23046579, 2522450, 24915922, 17015493, 22789865, 2147031, 2170400, 1386607, 2147027, 27021291, 20798201)
OMIM	RCV002286417	SCV000024245	pathogenic	Sandhoff disease, juvenile form	1990-10-15	no assertion criteria provided	literature only
Natera, Inc.	RCV000633008	SCV002084949	pathogenic	Sandhoff disease	2020-12-10	no assertion criteria provided	clinical testing