Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001910724 | SCV002187799 | uncertain significance | Holocarboxylase synthetase deficiency | 2021-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with serine at codon 609 of the HLCS protein (p.Pro609Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with HLCS-related conditions. 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 HLCS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004770284 | SCV005380809 | uncertain significance | not specified | 2024-08-08 | criteria provided, single submitter | clinical testing | Variant summary: HLCS c.1825C>T (p.Pro609Ser) results in a non-conservative amino acid change located in the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domain (IPR004143) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.1825C>T has been reported in the literature in at least two compound heterozygous individuals affected with Holocarboxylase Synthetase Deficiency (e.g., Ling_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36890565). ClinVar contains an entry for this variant (Variation ID: 1419930). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |