Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001058264 | SCV001222822 | likely pathogenic | Sandhoff disease | 2019-01-23 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with HEXB-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the HEXB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
| Baylor Genetics | RCV001058264 | SCV001520757 | pathogenic | Sandhoff disease | 2019-08-22 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001058264 | SCV002041578 | likely pathogenic | Sandhoff disease | 2021-11-23 | criteria provided, single submitter | clinical testing | Variant summary: HEXB c.558+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. Splice site variants downstream of this position are associated with Sandhoff disease in HGMD database. The variant was absent in 245680 control chromosomes (gnomAD). To our knowledge, no occurrence of c.558+1G>C in individuals affected with Sandhoff Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |