rs121909330

Positions:

• chr9-35065364-G-A
• chr9-35065364-G-C
• chr9-35065364-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000358901.11(VCP):​c.463C>T​(p.Arg155Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCP ENST00000358901.11 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.96

Genes affected

VCP (HGNC:12666): (valosin containing protein) This gene encodes a member of the AAA ATPase family of proteins. The encoded protein plays a role in protein degradation, intracellular membrane fusion, DNA repair and replication, regulation of the cell cycle, and activation of the NF-kappa B pathway. This protein forms a homohexameric complex that interacts with a variety of cofactors and extracts ubiquitinated proteins from lipid membranes or protein complexes. Mutations in this gene cause IBMPFD (inclusion body myopathy with paget disease of bone and frontotemporal dementia), ALS (amyotrophic lateral sclerosis) and Charcot-Marie-Tooth disease in human patients. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000358901.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-35065364-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCP. . Gene score misZ 5.4064 (greater than the threshold 3.09). Trascript score misZ 8.1614 (greater than threshold 3.09). GenCC has associacion of gene with spastic paraplegia-Paget disease of bone syndrome, adult-onset distal myopathy due to VCP mutation, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, Charcot-Marie-Tooth disease type 2Y, amyotrophic lateral sclerosis, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, frontotemporal dementia with motor neuron disease, inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 9-35065364-G-A is Pathogenic according to our data. Variant chr9-35065364-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35065364-G-A is described in Lovd as [Pathogenic]. Variant chr9-35065364-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCP	NM_007126.5	c.463C>T	p.Arg155Cys	missense_variant	5/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.328C>T	p.Arg110Cys	missense_variant	5/17		NP_001341856.1
VCP	NM_001354928.2	c.328C>T	p.Arg110Cys	missense_variant	5/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.463C>T	p.Arg155Cys	missense_variant	5/17	1	NM_007126.5	ENSP00000351777	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 05, 2024	PP1_strong, PP2, PP3, PM1, PM2, PM5, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2016	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. -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Mar 31, 2020

- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the VCP protein (p.Arg155Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) (PMID: 15034582, 16790606, 17763460, 19364651, 22909335, 26105173). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8469). 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: 16984901, 23056506, 27768726, 28360103). This variant disrupts the p.Arg155 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15034582, 23029473, 25388089). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.047	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.61		Loss of MoRF binding (P = 0.0045);.;.;
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.96
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909330; hg19: chr9-35065361; COSMIC: COSV62719858; COSMIC: COSV62719858;