rs121909332

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3PP5

The NM_007126.5(VCP):c.283C>T(p.Arg95Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

VCP
NM_007126.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 6.58

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-35067910-G-C is described in Lovd as [Pathogenic].

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, 0.752

PP5

Variant 9-35067910-G-A is Pathogenic according to our data. Variant chr9-35067910-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 280124.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=5}. Variant chr9-35067910-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VCP	NM_007126.5 linkuse as main transcript	c.283C>T	p.Arg95Cys	missense_variant	3/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2 linkuse as main transcript	c.148C>T	p.Arg50Cys	missense_variant	3/17		NP_001341856.1
VCP	NM_001354928.2 linkuse as main transcript	c.148C>T	p.Arg50Cys	missense_variant	3/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
VCP	ENST00000358901.11 linkuse as main transcript	c.283C>T	p.Arg95Cys	missense_variant	3/17	1	NM_007126.5	ENSP00000351777.6	P55072
ENSG00000288699	ENST00000681845.1 linkuse as main transcript	n.*381C>T		non_coding_transcript_exon_variant	3/5			ENSP00000505452.1	A0A7P0T910
ENSG00000288699	ENST00000681845.1 linkuse as main transcript	n.*381C>T		3_prime_UTR_variant	3/5			ENSP00000505452.1	A0A7P0T910

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2017	The R95C pathogenic variant in the VCP gene has been reported previously in association with IBMPFD (Kimonis et al., 2008; Juntas et al., 2009; Weihl et al., 2015). The R95C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R95C 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. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In vitro functional studies show that R95C is associated with an increase in ATPase activity and increased LC3-II and p62 protein levels, suggestive of a disruption of autophagosome maturation (Weihl et al., 2015). A missense variant affecting this same codon (R95G) has been reported in association with IBMPFD, supporting the functional importance of this residue of the protein (Watts et al., 2004). Missense variants in nearby residues (R93C, R93H, G97E) have also been reported in the Human Gene Mutation Database in association with VCP-related disorders (Stenson et al., 2014). We interpret R95C as a likely pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

Spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

May 26, 2016

- -

Amyotrophic lateral sclerosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Mar 31, 2020

- -

VCP-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

The VCP c.283C>T variant is predicted to result in the amino acid substitution p.Arg95Cys. This variant has been reported in patients with inclusion body myopathy or frontotemporal dementia (Kimonis et al. 2008. PubMed ID: 18845250; Weihl et al. 2015. PubMed ID: 25617006; Artan et al. 2021. PubMed ID: 34162492). Enzymatic studies showed this variant enhanced VCP activity and in vitro expression studies showed this variant increased autophagy (Weihl et al. 2015. PubMed ID: 25617006). A different missense change at the same amino acid position (p.Arg95Gly) has previously been reported to be causative for inclusion body myopathy (Mehta et al. 2012. PubMed ID: 22909335). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

May 29, 2024

- -

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

Jul 25, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg95 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15034582, 20604808, 22270372, 22909335, 23333620). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects VCP function (PMID: 25617006). 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 expected to disrupt VCP protein function. ClinVar contains an entry for this variant (Variation ID: 280124). This missense change has been observed in individuals with clinical features of VCP-related conditions (PMID: 25617006; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909332, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 95 of the VCP protein (p.Arg95Cys). -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2021

The p.R95C variant (also known as c.283C>T), located in coding exon 3 of the VCP gene, results from a C to T substitution at nucleotide position 283. The arginine at codon 95 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in families with VCP-related disorders, including inclusive body myopathy with Paget disease and frontotemporal dementia (IBMPFD) and peripheral neuropathy with progressive muscle pain (Kimonis VE et al. Biochim Biophys Acta, 2008 Dec;1782:744-8; Weihl CC et al. Neuromuscul Disord, 2015 Apr;25:289-96; Senderek J et al. Neurology, 2020 12;95:e3163-e3179). Another alteration at the same codon, p.R95G (c.283C>G), has been described in a family with IBMPFD and may impact protein function (Watts GD et al. Nat Genet, 2004 Apr;36:377-81; Weihl CC et al. Hum Mol Genet, 2006 Jan;15:189-99; Erzurumlu Y et al. Int J Biochem Cell Biol, 2013 Apr;45:773-82; Niwa H et al. J Biol Chem, 2012 Mar;287:8561-70). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.2

D;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.040

D;D;D

Sift4G

Benign

0.19

T;.;.

Polyphen

0.40

B;.;.

Vest4

0.49

MutPred

0.67

Loss of MoRF binding (P = 0.0414);.;.;

MVP

0.83

MPC

2.1

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.82

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