9-35065363-C-T

Position:

• chr9-35065363-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_007126.5(VCP):​c.464G>A​(p.Arg155His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R155L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.77

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.874
• PP5: Variant 9-35065363-C-T is Pathogenic according to our data. Variant chr9-35065363-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35065363-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCP	NM_007126.5	c.464G>A	p.Arg155His	missense_variant	5/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.329G>A	p.Arg110His	missense_variant	5/17		NP_001341856.1
VCP	NM_001354928.2	c.329G>A	p.Arg110His	missense_variant	5/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.464G>A	p.Arg155His	missense_variant	5/17	1	NM_007126.5	ENSP00000351777	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 09, 2015	- -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 09, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Feb 09, 2017	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

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. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 09, 2010

- -

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

Dec 24, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.17	T;.;.
Polyphen		0.95	P;.;.
Vest4		0.89
MutPred		0.64		Loss of MoRF binding (P = 0.0084);.;.;
MVP		0.97
MPC		1.7
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.80
gMVP		0.85

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: rs121909329; hg19: chr9-35065360;