Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000427051 | SCV000521181 | likely pathogenic | not provided | 2016-03-11 | criteria provided, single submitter | clinical testing | The Y266D variant in the HEXB gene has been reported previously in association with Sandoff disease when present in the homozygous state or when in trans with another pathogenic variant (Maegawa et al., 2006; Gort et al., 2012). The Y266D variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y266D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The Y266D variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Fulgent Genetics, |
RCV000669074 | SCV000894361 | pathogenic | Sandhoff disease | 2021-12-14 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000669074 | SCV001579761 | pathogenic | Sandhoff disease | 2023-09-21 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 266 of the HEXB protein (p.Tyr266Asp). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXB protein function. ClinVar contains an entry for this variant (Variation ID: 381669). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 17015493, 22789865, 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 present in population databases (rs373979283, gnomAD 0.005%). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000669074 | SCV002041583 | pathogenic | Sandhoff disease | 2021-11-28 | criteria provided, single submitter | clinical testing | Variant summary: HEXB c.796T>G (p.Tyr266Asp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251446 control chromosomes. c.796T>G has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Sandhoff Disease (example, Gort_2012, Mugnaini_2017, Gaignard_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Gort_2012). The most pronounced variant effect results in <10% of normal total Hexosaminidase activity in serum and fibroblasts of an affected individual with a homozygous genotype. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Counsyl | RCV000669074 | SCV000793776 | likely pathogenic | Sandhoff disease | 2017-08-31 | no assertion criteria provided | clinical testing |