Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000669070 | SCV000793771 | likely pathogenic | Holocarboxylase synthetase deficiency | 2017-08-30 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000669070 | SCV003003599 | likely pathogenic | Holocarboxylase synthetase deficiency | 2022-03-09 | criteria provided, single submitter | clinical testing | This variant disrupts a region of the HLCS protein in which other variant(s) (p.Pro709Leu) have been observed in individuals with HLCS-related conditions (PMID: 27604308). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects HLCS function (PMID: 11124959). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 553590). This variant is also known as a 31-amino acid deletion ending at Leu-695. This variant has not been reported in the literature in individuals affected with HLCS-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln696*) in the HLCS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the HLCS protein. 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. |