Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000669592 | SCV000794361 | uncertain significance | Tay-Sachs disease | 2017-10-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001584543 | SCV001821429 | uncertain significance | not specified | 2023-01-20 | criteria provided, single submitter | clinical testing | Variant summary: HEXA c.1074-7_1074-3delTCTCC removes 5 nucleotides, thus shortening the length of the polypyrimidine tract located in intron 9, 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 weakens a 3' acceptor site, while one predicts the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes (gnomAD). c.1074-7_1074-3delTCTCC has been reported in the literature in a family in 3 individuals affected with Tay-Sachs Disease, who also carried a pathogenic variant in trans (Triggs-Raine_1991). Though the authors of this study noted that their preliminary results showed that this mutation results in aberrant splicing, they also added that further studies are required to confirm these findings. Other variants shortening the polypyrimidine tract in intron 12 of the HEXA gene were demonstrated to result in exon skipping, when an exonic variant was also present at the first position of exon 13 (Fu_2011), however these data do not provide clear conclusions about the effect of the variant of interest. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Labcorp Genetics |
RCV000669592 | SCV004297642 | likely pathogenic | Tay-Sachs disease | 2023-05-12 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 554039). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 1833974). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs759219683, gnomAD 0.0009%). This sequence change falls in intron 9 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| OMIM | RCV000669592 | SCV000024281 | affects | Tay-Sachs disease | 1991-11-01 | no assertion criteria provided | literature only |