9-35065351-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_007126.5(VCP):c.476G>A(p.Arg159His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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. R159S) has been classified as 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:14

Conservation

PhyloP100: 7.77

Publications

64 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
inclusion body myopathy with Paget disease of bone and frontotemporal dementia
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Charcot-Marie-Tooth disease type 2Y
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
frontotemporal dementia and/or amyotrophic lateral sclerosis 6
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
adult-onset distal myopathy due to VCP mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
frontotemporal dementia with motor neuron disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spastic paraplegia-Paget disease of bone syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

VCP links:

ENSG00000288699 (HGNC:):

ENSG00000288699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_007126.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-35065352-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 989439.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.817

PP5

Variant 9-35065351-C-T is Pathogenic according to our data. Variant chr9-35065351-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VCP	NM_007126.5 link	c.476G>A	p.Arg159His	missense_variant	Exon 5 of 17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 link	c.341G>A	p.Arg114His	missense_variant	Exon 5 of 17		NP_001341856.1
VCP	NM_001354928.2 link	c.341G>A	p.Arg114His	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.476G>A	p.Arg159His	missense_variant	Exon 5 of 17	1	NM_007126.5	ENSP00000351777.6	P55072
ENSG00000288699	ENST00000681845.1 link	n.*574G>A		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000505452.1	A0A7P0T910
ENSG00000288699	ENST00000681845.1 link	n.*574G>A		3_prime_UTR_variant	Exon 5 of 5			ENSP00000505452.1	A0A7P0T910

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251462

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Jun 08, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VCP: PM2, PM5, PS4:Moderate, PP1, PP2, PP3, PS3:Supporting -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely pathogenic

Review Status:no assertion criteria provided

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

- -

Oct 22, 2018

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R159H variant in the VCP gene has been reported previously in association with inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as both sporadic and familial forms of amyotrophic lateral sclerosis (Haubenberger et al., 2005; Ayaki et al., 2014; van der Zee et al., 2009). In vitro expression studies of the R159H variant in SH-SY5Y cells showed a statistically significant increase in the percentage of cells with cytoplasmic TDP-43; translocation of TDP-43 to the cytoplasm and aggregation in the cytoplasm has previously been reported as a feature of VCP-related ALS (Ayaki et al., 2014). The R159H variant is observed in 1/22300 alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). Although the R159H variant is a conservative amino acid substitution, it occurs in the four-stranded b barrel in the CDC48 domain, a critical functional domain (Hubbers et al., 2007). We interpret R159H as a pathogenic variant. -

Oct 26, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). It is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant has been identified in multiple unrelated individuals with clinical features of FTD/ALS as well as IBMPFD. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMIDs: 22270372, 27226613, 25492614) The variant is located in a region that is considered important for protein function and/or structure. -

Apr 28, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP2, PS3, PS4 -

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

Pathogenic:3

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 14, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). 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: 0.60 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=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: VCV000008474 /PMID: 16247064). Different missense changes at the same codon (p.Arg159Cys, p.Arg159Gly, p.Arg159Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030152, VCV000280123, VCV000989439 /PMID: 17889967, 21145000, 30103325). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

VCP-related disorder

Pathogenic:1

Apr 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The VCP c.476G>A variant is predicted to result in the amino acid substitution p.Arg159His. This variant is reported to be causative for progressive proximal myopathy and Paget disease of the bone in four affected members of an Australian family (Haubenberger et al. 2005. PubMed ID: 16247064). It was also reported to be causative for inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) (van der Zee et al. 2009. PubMed ID: 19704082). In vitro functional studies in HEK293T and SH-SY5Y cells have demonstrated that expression of this variant results in TDP-43 mislocalization (Figure 6, Ayaki et al. 2014. PubMed ID: 25492614). The c.476G>A variant has also been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/8474/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Pathogenic:1

Jan 23, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:1

Jan 18, 2025

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 159 of the VCP protein (p.Arg159His). This variant is present in population databases (rs121909335, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD) (PMID: 16247064, 19225410, 19704082, 22078486, 24829604, 26555887). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8474). 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: 22270372, 25492614, 26555887, 27226613). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

0.58

MutationAssessor

Uncertain

2.5

M;.;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.60

Sift

Benign

0.095

T;T;T

Sift4G

Benign

0.15

T;.;.

Polyphen

0.52

P;.;.

Vest4

0.69

MutPred

0.61

Loss of MoRF binding (P = 0.0208);.;.;

MVP

0.96

MPC

1.7

ClinPred

0.90

GERP RS

6.1

PromoterAI

-0.0080

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.8

Varity_R

0.80

gMVP

0.87

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over