Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001949225 | SCV002240739 | pathogenic | Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia | 2022-07-19 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Arg155 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15034582, 16790606, 17763460, 19364651, 26105173). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 VCP protein function. ClinVar contains an entry for this variant (Variation ID: 1457380). This missense change has been observed in individuals with clinical features of VCP-related conditions (PMID: 19364651, 30488450). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 155 of the VCP protein (p.Arg155Ser). For these reasons, this variant has been classified as Pathogenic. |