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

dbSNP: rs121909330

Total submissions: 7

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	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the VCP protein (p.Arg155Cys). This variant is not present in population databases (gnomAD 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 not expected to disrupt VCP protein function with a negative predictive value of 80%. 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
Revvity Omics, Revvity	RCV000372207	SCV002020856	pathogenic	not provided	2020-06-30	criteria provided, single submitter	clinical testing
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