NM_007126.5:c.464G>A

Variant names:

• chr9-35065363-C-T
• rs121909329
• NM_007126.5:c.464G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007126.5(VCP):​c.464G>A​(p.Arg155His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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 (★★). ClinVar reports functional evidence for this variant: "SCV000617827: Published functional studies indicate that R155H results in altered protein conformation and cofactor association, as well as elevated ATPase activity (Zhang et al., 2015)" and additional evidence is available in ClinVar. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 7.77
• Publications: 208 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: Orphanet, ClinGen
• Charcot-Marie-Tooth disease type 2Y

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• frontotemporal dementia and/or amyotrophic lateral sclerosis 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617827: Published functional studies indicate that R155H results in altered protein conformation and cofactor association, as well as elevated ATPase activity (Zhang et al., 2015); Published functional studies showed cells expressing R155H accumulated autophagosomes that coalesce at rimmed vacuoles and failed to degrade aggregated proteins (Ju et al., 2009).; SCV000638348: Experimental studies have shown that this missense change affects VCP function (PMID: 19237541, 20604808, 23029473, 23498975, 25125609, 25388089, 25775548).; SCV002635321: Functional studies demonstrated that the p.R155H alteration exhibited elevated ATPase activities compared to wild-type (Manno A et al. Genes Cells, 2010 Aug;15:911-22; Zhang X et al. Proc Natl Acad Sci U S A, 2015 Apr;112:E1705-14).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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, 0.874
• PP5: Variant 9-35065363-C-T is Pathogenic according to our data. Variant chr9-35065363-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8468.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	NM_007126.5	MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 17	NP_009057.1	P55072
	VCP	NM_001354927.2		c.329G>A	p.Arg110His	missense	Exon 5 of 17	NP_001341856.1	C9JUP7
	VCP	NM_001354928.2		c.329G>A	p.Arg110His	missense	Exon 5 of 17	NP_001341857.1	C9JUP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCP	ENST00000358901.11	TSL:1 MANE Select	c.464G>A	p.Arg155His	missense	Exon 5 of 17	ENSP00000351777.6	P55072
	ENSG00000288699	ENST00000681845.1		n.*562G>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000505452.1	A0A7P0T910
	ENSG00000288699	ENST00000681845.1		n.*562G>A		3_prime_UTR	Exon 5 of 5	ENSP00000505452.1	A0A7P0T910

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
4	-	-	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 (4)
1	-	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.73
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.95	P
Vest4		0.89
MutPred		0.64		Loss of MoRF binding (P = 0.0084)
MVP		0.97
MPC		1.7
ClinPred		0.99	D
GERP RS		6.1
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.80
gMVP		0.85
Mutation Taster		=7/93	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: rs121909329; hg19: chr9-35065360;