Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000665204 | SCV000789280 | likely pathogenic | Sandhoff disease | 2017-01-19 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000665204 | SCV002041581 | likely pathogenic | Sandhoff disease | 2021-11-23 | criteria provided, single submitter | clinical testing | Variant summary: HEXB c.1611_1613+2delCGAGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site and predict the variant creates a 5 prime donor site that is out-of-frame with the canonical splice site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251220 control chromosomes. To our knowledge, no occurrence of c.1611_1613+2delCGAGT in individuals affected with Sandhoff Disease and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has classified this variant (after 2014) and they assessed the variant to be likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV000665204 | SCV003783912 | pathogenic | Sandhoff disease | 2022-04-13 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Val537Thrfs*14) in the HEXB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acids of the HEXB protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HEXB-related conditions. This variant is also known as c.1611_1613+2del. ClinVar contains an entry for this variant (Variation ID: 550455). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the HEXB protein in which other variant(s) (p.Gly549Arg) have been determined to be pathogenic (PMID: 24022928, 27021291, 28281504). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |