ClinVar Miner

Submissions for variant NM_007126.5(VCP):c.464G>A (p.Arg155His) (rs121909329)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523065 SCV000617827 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The R155H variant in the VCP gene has been reported previously in the heterozygous state in individuals with IBMPFD in multiple generations of unrelated families (Watts et al., 2004; Stojkovic et al., 2009). The R155H variant is not observed in large population cohorts (Lek et al., 2016). The R155H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. The accumulation of aggregated proteins and autophagosomes were observed in transgenic mutant R155H murine cells and in vitro studies showed R155H altered the N-domain conformation, elevated ATPase activity, and altered cofactor association (Ju et al., 2009; Zhang et al., 2015). Different pathogenic missense variants at the same codon (R155G; R155C) have been reported in the Human Gene Mutation Database in association with a VCP-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R155H as a pathogenic variant, consistent with the diagnosis of a VCP-related disorder and the likely explanation for the muscle weakness and cramps reported in this individual.
Invitae RCV000540496 SCV000638348 pathogenic Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 155 of the VCP protein (p.Arg155His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in several large multigenerational families affected with inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) (PMID: 15034582). ClinVar contains an entry for this variant (Variation ID: 8468). Experimental studies have shown that this missense change affects the structure and function of the VCP protein, and also leads to the formation of protein aggregates (PMID: 19237541, 20604808, 23498975, 25125609, 25775548). In addition, mouse models carrying this variant recapitulate a phenotype similar to IBMPFD (PMID: 25388089, 23029473). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000523065 SCV000707858 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000008989 SCV000778401 pathogenic Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 2017-02-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000523065 SCV000844851 pathogenic not provided 2015-01-09 criteria provided, single submitter clinical testing
OMIM RCV000008989 SCV000029203 pathogenic Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1 2010-12-09 no assertion criteria provided literature only
OMIM RCV000023063 SCV000044354 pathogenic Amyotrophic lateral sclerosis 14 without frontotemporal dementia 2010-12-09 no assertion criteria provided literature only

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