ClinVar Miner

Submissions for variant NM_007126.5(VCP):c.463C>T (p.Arg155Cys) (rs121909330)

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Total submissions: 6
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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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000372207 SCV000709574 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing
Invitae RCV000685660 SCV000813149 pathogenic Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia; Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 2019-12-16 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 variant has been reported to segregate with inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) in many families (PMID: 19364651, 15034582, 17763460, 26105173, 16790606). This variant is one of the most common pathogenic variants in VCP causing IBMPFD (PMID: 22909335). ClinVar contains an entry for this variant (Variation ID: 8469). Experimental studies have shown that this missense change alters protein structure and function (PMID: 16984901, 28360103, 23056506, 27768726). A different missense substitution at this codon (p.Arg155His) has been determined to be pathogenic (PMID: 15034582, 25388089, 23029473). This suggests that the arginine residue is critical for VCP protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000372207 SCV001248049 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory,Koc University RCV001095424 SCV001251001 likely pathogenic Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia 2020-03-31 criteria provided, single submitter research
OMIM RCV000008990 SCV000029204 pathogenic Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 2011-06-01 no assertion criteria provided literature only

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