Submissions for variant NM_007126.5(VCP):c.463C>G (p.Arg155Gly)

dbSNP: rs121909330

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000196145	SCV000255505	likely pathogenic	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	2013-06-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000494556	SCV000581735	pathogenic	not provided	2017-05-04	criteria provided, single submitter	clinical testing	The R155G variant in the VCP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The R155G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R155G 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R155S, R155C, R155L, R155H, R155P) have been reported previously in the heterozygous state in individuals with VCP-related disorders (Stojkovic et al., 2009; Kumar et al., 2010; Watts et al., 2004). Additionally, missense variants in nearby residues (I151V, G156C, G156S, G157R, M158V, R159C, R159G, R159H) have also been reported in the Human Gene Mutation Database in association with VCP-related disorders (Stenson et al., 2014). These variants support the functional importance of this region of the protein. Therefore, we interpret R155G as a pathogenic variant.
Invitae	RCV002229498	SCV000940847	likely pathogenic	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	2022-08-09	criteria provided, single submitter	clinical testing	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: 217028). This missense change has been observed in individual(s) with myopathy (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 155 of the VCP protein (p.Arg155Gly). 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. 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.