rs121909332

Positions:

• chr9-35067910-G-A
• chr9-35067910-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 6.58

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr9-35067909-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1513178.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, VCP
• 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, Likely_pathogenic=5, Pathogenic=3}. Variant chr9-35067910-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCP	NM_007126.5	c.283C>T	p.Arg95Cys	missense_variant	3/17	ENST00000358901.11
VCP	NM_001354927.2	c.148C>T	p.Arg50Cys	missense_variant	3/17
VCP	NM_001354928.2	c.148C>T	p.Arg50Cys	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCP	ENST00000358901.11	c.283C>T	p.Arg95Cys	missense_variant	3/17	1	NM_007126.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251464 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

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: 3 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2021	- -

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

- -

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

Invitae

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	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	34
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	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.40	T
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	D
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

Other links and lift over

dbSNP: rs121909332; hg19: chr9-35067907;