9-35065363-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.77

Variant links:

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]

VCP links:

ENSG00000288699 (HGNC:):

ENSG00000288699 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 the VCP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 5.4064 (above the threshold of 3.09). Trascript score misZ: 8.1614 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein
VCP	NM_007126.5 link	c.464G>A	p.Arg155His	missense_variant	Exon 5 of 17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 link	c.329G>A	p.Arg110His	missense_variant	Exon 5 of 17		NP_001341856.1
VCP	NM_001354928.2 link	c.329G>A	p.Arg110His	missense_variant	Exon 5 of 17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VCP	ENST00000358901.11 link	c.464G>A	p.Arg155His	missense_variant	Exon 5 of 17	1	NM_007126.5	ENSP00000351777.6	P55072
ENSG00000288699	ENST00000681845.1 link	n.*562G>A		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000505452.1	A0A7P0T910
ENSG00000288699	ENST00000681845.1 link	n.*562G>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000505452.1	A0A7P0T910

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Mar 25, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Aug 16, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 09, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:4

Dec 09, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 04, 2022

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008468 /PMID: 15034582). Different missense changes at the same codon (p.Arg155Cys, p.Arg155Gly, p.Arg155Leu, p.Arg155Pro, p.Arg155Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008469, VCV000008472, VCV000217028, VCV001457380 /PMID: 15034582, 19364651, 20335036, 25326637). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases

Pathogenic:1

Oct 29, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Pathogenic:1

Dec 09, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

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

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.8

M;.;.

PrimateAI

Pathogenic

0.93

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over