9-35065364-G-C

Variant names:

• chr9-35065364-G-C
• rs121909330
• NM_007126.5:c.463C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007126.5(VCP):​c.463C>G​(p.Arg155Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R155P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.96
• Publications: 113 publications found

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

ENSG00000288699 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr9-35065363-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8472.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 9-35065364-G-C is Pathogenic according to our data. Variant chr9-35065364-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007126.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	NM_007126.5	MANE Select	c.463C>G	p.Arg155Gly	missense	Exon 5 of 17	NP_009057.1
	VCP	NM_001354927.2		c.328C>G	p.Arg110Gly	missense	Exon 5 of 17	NP_001341856.1
	VCP	NM_001354928.2		c.328C>G	p.Arg110Gly	missense	Exon 5 of 17	NP_001341857.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.463C>G	p.Arg155Gly	missense	Exon 5 of 17	ENSP00000351777.6
	ENSG00000288699	ENST00000681845.1		n.*561C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000505452.1
	ENSG00000288699	ENST00000681845.1		n.*561C>G		3_prime_UTR	Exon 5 of 5	ENSP00000505452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jun 25, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

May 04, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R155G variant in the VCP gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The R155G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R155G 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 that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R155S, R155C, R155L, R155H, R155P) have been reported previously in the heterozygous state in individuals with VCP-related disorders (Stojkovic et al., 2009; Kumar et al., 2010; Watts et al., 2004). Additionally, missense variants in nearby residues (I151V, G156C, G156S, G157R, M158V, R159C, R159G, R159H) have also been reported in the Human Gene Mutation Database in association with VCP-related disorders (Stenson et al., 2014). These variants support the functional importance of this region of the protein. Therefore, we interpret R155G as a pathogenic variant.

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 217028). This missense change has been observed in individual(s) with myopathy (PMID: 25326637). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 155 of the VCP protein (p.Arg155Gly). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg155 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15034582, 16790606, 17763460, 19364651, 26105173). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.82
Sift	Benign	0.097	T
Sift4G	Benign	0.27	T
Polyphen		0.99	D
Vest4		0.84
MutPred		0.59		Loss of MoRF binding (P = 0.0054)
MVP		0.98
MPC		2.5
ClinPred		0.98	D
GERP RS		6.1
PromoterAI		0.0030	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.98
gMVP		0.96
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909330; hg19: chr9-35065361;