ClinVar Miner

Submissions for variant NM_007126.5(VCP):c.463C>T (p.Arg155Cys)

dbSNP: rs121909330
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000372207 SCV000329986 pathogenic not provided 2016-06-23 criteria provided, single submitter clinical testing The R155C pathogenic variant in the VCP gene has been reported previously in the heterozygous state as the most common variant among individuals with Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia (IBMPFD) (Watts et al., 2004; Schröder et al., 2005; Guyant-Maréchal et al., 2006; Kim et al., 2011). The R155C variant was not observed in approximately 6500 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 R155C 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 and this substitution occurs at a position that is that is conserved across species. Functional studies show that R155C causes loss of function in an in vitro culture model of frontotemporal lobar dementia (Gitcho et al., 2009) and studies using patient fibroblasts harboring the R155C variant show mitochondrial uncoupling resulting in reduced cellular ATP production (Bartolome et al., 2013). Missense variants affecting the same codon (R155H, R155P, R155S, R155L) and other nearby residues (I151V, G156S, G156C, G157R, M158V, R159G, R159C, R159H) have been reported in the Human Gene Mutation Database in association with VCP-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R155C as a pathogenic variant.
Eurofins NTD LLC (GA) RCV000372207 SCV000709574 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing
Invitae RCV000685660 SCV000813149 pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia 2021-08-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 155 of the VCP protein (p.Arg155Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) (PMID: 15034582, 16790606, 17763460, 19364651, 22909335, 26105173). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8469). 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. Experimental studies have shown that this missense change affects VCP function (PMID: 16984901, 23056506, 27768726, 28360103). 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, 23029473, 25388089). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000372207 SCV001248049 pathogenic not provided 2021-04-01 criteria provided, single submitter clinical testing
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University RCV001095424 SCV001251001 likely pathogenic Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 2020-03-31 criteria provided, single submitter research
OMIM RCV000008990 SCV000029204 pathogenic Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 2011-06-01 no assertion criteria provided literature only
PerkinElmer Genomics RCV000372207 SCV002020856 pathogenic not provided 2020-06-30 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.