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

dbSNP: rs121909329

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523065	SCV000617827	pathogenic	not provided	2021-03-25	criteria provided, single submitter	clinical testing	Published functional studies indicate that R155H results in altered protein conformation and cofactor association, as well as elevated ATPase activity (Zhang et al., 2015); Published functional studies showed cells expressing R155H accumulated autophagosomes that coalesce at rimmed vacuoles and failed to degrade aggregated proteins (Ju et al., 2009); Published transgenic and knock-in mouse models recapitulate the IBMPFD phenotype (Custer et al., 2010; Nalbandian et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25492614, 25457024, 25388089, 29091718, 28877744, 28430856, 30293881, 16984901, 29382405, 23169451, 20104022, 22686199, 20604808, 19237541, 24196964, 22270372, 20008565, 21822278, 23498975, 25775548, 19364651, 25125609, 21145000, 15034582, 29650794, 23635965, 31687228, 20147319, 23029473, 18341608)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540496	SCV000638348	pathogenic	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 155 of the VCP protein (p.Arg155His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) (PMID: 15034582). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8468). 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: 19237541, 20604808, 23029473, 23498975, 25125609, 25388089, 25775548). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	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 Paget disease of bone and frontotemporal dementia type 1	2017-02-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000523065	SCV000844851	pathogenic	not provided	2015-01-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000523065	SCV002020858	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336080	SCV002635321	pathogenic	Inborn genetic diseases	2021-10-29	criteria provided, single submitter	clinical testing	The p.R155H pathogenic mutation (also known as c.464G>A), located in coding exon 5 of the VCP gene, results from a G to A substitution at nucleotide position 464. The arginine at codon 155 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported to segregate with disease in multiple unrelated families with features of dominantly inherited VCP-related disorders, including inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) (Jerath NU. Case Rep Genet, 2019 Oct;2019:2403024; Pinto WBVR et al. Rev Neurol (Paris), 2019 Apr;175:238-246; Viassolo V et al. Clin Genet, 2008 Jul;74:54-60; Watts GD et al. Nat Genet, 2004 Apr;36:377-81). Functional studies demonstrated that the p.R155H alteration exhibited elevated ATPase activities compared to wild-type (Manno A et al. Genes Cells, 2010 Aug;15:911-22; Zhang X et al. Proc Natl Acad Sci U S A, 2015 Apr;112:E1705-14). Mouse knock-in models harboring the p.R155H alteration recapitulated the phenotype observed in VCP-related disorders (Badadani M et al. PLoS One, 2010 Oct;5(10):e13183; Nalbandian A et al. Muscle Nerve, 2013 Feb;47:260-70; Yin HZ et al. Cell Death Dis, 2012 Aug;3:e374). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD) and is also predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000008989	SCV002764944	pathogenic	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	2022-08-04	criteria provided, single submitter	clinical testing
OMIM	RCV000008989	SCV000029203	pathogenic	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	2010-12-09	no assertion criteria provided	literature only
OMIM	RCV001271089	SCV001451911	pathogenic	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6	2010-12-09	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000523065	SCV001926460	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000523065	SCV001951590	pathogenic	not provided		no assertion criteria provided	clinical testing