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

dbSNP: rs387906789

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000333881	SCV000329985	pathogenic	not provided	2019-04-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the R159C mutant protein results in substrate accumulation and reduced endoplasmic reticulum associated degradation (Erzurumlu et al., 2013).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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 is associated with the following publications: (PMID: 22572540, 21816654, 22991237, 23333620, 17889967, 22900631, 27594680, 28542158, 30279455, 28692196)
Invitae	RCV002229732	SCV000937452	pathogenic	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 159 of the VCP protein (p.Arg159Cys). This variant is present in population databases (rs387906789, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of VCP-related conditions (PMID: 17889967, 21816654, 23152587, 28692196). ClinVar contains an entry for this variant (Variation ID: 280123). 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 not expected to disrupt VCP protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects VCP function (PMID: 23333620). This variant disrupts the p.Arg159 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16247064, 19704082, 22270372, 24829604, 25492614, 26555887, 27226613). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	RCV001095425	SCV001251002	likely pathogenic	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6	2020-03-31	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000333881	SCV002020860	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000333881	SCV001926316	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000333881	SCV001954088	pathogenic	not provided		no assertion criteria provided	clinical testing