ClinVar Miner

Submissions for variant NM_007126.5(VCP):c.475C>T (p.Arg159Cys) (rs387906789)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000333881 SCV000329985 pathogenic not provided 2016-07-26 criteria provided, single submitter clinical testing The R159C pathogenic variant in the VCP gene has been reported previously in several individuals with inclusion body myopathy with Paget's disease of bone and frontotemporal demantia (IBMPFD) (Spina et al., 2013; Bersano et al., 2009). This 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 R159C variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that the R159C mutant protein results in substrate accumulation and reduced endoplasmic reticulum associated degradation (Erzurumlu et al., 2013). Missense variants in the same residue (R159G, R159H) and nearby residues (R155S, R155C, R155L, R155H, R155P, G156S, G157R, M158V) have been reported in the Human Gene Mutation Database in association with IBMPFD and ALS (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R159C as a pathogenic variant.
Invitae RCV000797868 SCV000937452 pathogenic Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia 2018-07-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 159 of the VCP protein (p.Arg159Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs387906789, ExAC 0.001%). This variant has been observed in several individuals and families affected with inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) (PMID: 17889967, 21816654, 28692196, 23152587). ClinVar contains an entry for this variant (Variation ID: 280123). Experimental studies have shown that this missense change alters the endoplasmic reticulum associated degradation (ERAD) properties of the VCP protein (PMID: 23333620). Variants that disrupt the p.Arg159 amino acid residue in VCP have been observed in affected individuals (PMID: 19704082, 16247064, 24829604, 26555887, 27226613, 25492614, 22270372). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory,Koc University RCV001095425 SCV001251002 likely pathogenic Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia 2020-03-31 criteria provided, single submitter research

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