rs387906789

chr9-35065352-G-Achr9-35065352-G-Cchr9-35065352-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 NM_007126.5(VCP):c.475C>T(p.Arg159Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R159G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.64

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, 6 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 chr9-35065351-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, VCP
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 9-35065352-G-A is Pathogenic according to our data. Variant chr9-35065352-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35065352-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCP	NM_007126.5	c.475C>T	p.Arg159Cys	missense_variant	5/17	ENST00000358901.11
VCP	NM_001354927.2	c.340C>T	p.Arg114Cys	missense_variant	5/17
VCP	NM_001354928.2	c.340C>T	p.Arg114Cys	missense_variant	5/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCP	ENST00000358901.11	c.475C>T	p.Arg159Cys	missense_variant	5/17	1	NM_007126.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

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: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2019	Published functional studies demonstrate that the R159C mutant protein results in substrate accumulation and reduced endoplasmic reticulum associated degradation (Erzurumlu et al., 2013).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported previously in several individuals with inclusion body myopathy with Paget's disease of bone and frontotemporal demantia (IBMPFD) (Spina et al., 2013; Bersano et al., 2009).; This variant is associated with the following publications: (PMID: 22572540, 21816654, 22991237, 23333620, 17889967, 22900631, 27594680, 28542158, 30279455, 28692196) -
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+	-	- -

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

Invitae

Nov 30, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 159 of the VCP protein (p.Arg159Cys). This variant is present in population databases (rs387906789, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of VCP-related conditions (PMID: 17889967, 21816654, 23152587, 28692196). ClinVar contains an entry for this variant (Variation ID: 280123). 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: 23333620). This variant disrupts the p.Arg159 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16247064, 19704082, 22270372, 24829604, 25492614, 26555887, 27226613). 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	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.011	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.65		Loss of MoRF binding (P = 0.0128);.;.;
MVP		0.97
MPC		3.0
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.89
gMVP		0.93

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: rs387906789; hg19: chr9-35065349; COSMIC: COSV62721945; COSMIC: COSV62721945;