ClinVar Genomic variation as it relates to human health

The R95C pathogenic variant in the VCP gene has been reported previously in association with IBMPFD (Kimonis et al., 2008; Juntas et al., 2009; Weihl et al., 2015). The R95C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R95C 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 where amino acids with similar properties to Arginine are tolerated across species. In vitro functional studies show that R95C is associated with an increase in ATPase activity and increased LC3-II and p62 protein levels, suggestive of a disruption of autophagosome maturation (Weihl et al., 2015). A missense variant affecting this same codon (R95G) has been reported in association with IBMPFD, supporting the functional importance of this residue of the protein (Watts et al., 2004). Missense variants in nearby residues (R93C, R93H, G97E) have also been reported in the Human Gene Mutation Database in association with VCP-related disorders (Stenson et al., 2014). We interpret R95C as a likely pathogenic variant.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg95 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15034582, 20604808, 22270372, 22909335, 23333620). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects VCP function (PMID: 25617006). 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: 280124). This missense change has been observed in individuals with clinical features of VCP-related conditions (PMID: 25617006; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909332, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 95 of the VCP protein (p.Arg95Cys).

The p.R95C variant (also known as c.283C>T), located in coding exon 3 of the VCP gene, results from a C to T substitution at nucleotide position 283. The arginine at codon 95 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in families with VCP-related disorders, including inclusive body myopathy with Paget disease and frontotemporal dementia (IBMPFD) and peripheral neuropathy with progressive muscle pain (Kimonis VE et al. Biochim Biophys Acta, 2008 Dec;1782:744-8; Weihl CC et al. Neuromuscul Disord, 2015 Apr;25:289-96; Senderek J et al. Neurology, 2020 12;95:e3163-e3179). Another alteration at the same codon, p.R95G (c.283C>G), has been described in a family with IBMPFD and may impact protein function (Watts GD et al. Nat Genet, 2004 Apr;36:377-81; Weihl CC et al. Hum Mol Genet, 2006 Jan;15:189-99; Erzurumlu Y et al. Int J Biochem Cell Biol, 2013 Apr;45:773-82; Niwa H et al. J Biol Chem, 2012 Mar;287:8561-70). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The VCP c.283C>T variant is predicted to result in the amino acid substitution p.Arg95Cys. This variant has been reported in patients with inclusion body myopathy or frontotemporal dementia (Kimonis et al. 2008. PubMed ID: 18845250; Weihl et al. 2015. PubMed ID: 25617006; Artan et al. 2021. PubMed ID: 34162492). Enzymatic studies showed this variant enhanced VCP activity and in vitro expression studies showed this variant increased autophagy (Weihl et al. 2015. PubMed ID: 25617006). A different missense change at the same amino acid position (p.Arg95Gly) has previously been reported to be causative for inclusion body myopathy (Mehta et al. 2012. PubMed ID: 22909335). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.