rs121909335

Positions:

• chr9-35065351-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_007126.5(VCP):​c.476G>A​(p.Arg159His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159C) has been classified as 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

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]

ENSG00000288699 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 2) in uniprot entity TERA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr9-35065352-G-A 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, 0.817
• PP5: Variant 9-35065351-C-T is Pathogenic according to our data. 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. Variant chr9-35065351-C-T is described in Lovd as [Pathogenic]. Variant chr9-35065351-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCP	NM_007126.5	c.476G>A	p.Arg159His	missense_variant	5/17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.341G>A	p.Arg114His	missense_variant	5/17		NP_001341856.1
VCP	NM_001354928.2	c.341G>A	p.Arg114His	missense_variant	5/17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.476G>A	p.Arg159His	missense_variant	5/17	1	NM_007126.5	ENSP00000351777.6
ENSG00000288699	ENST00000681845.1	n.*574G>A		non_coding_transcript_exon_variant	5/5			ENSP00000505452.1
ENSG00000288699	ENST00000681845.1	n.*574G>A		3_prime_UTR_variant	5/5			ENSP00000505452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251462 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135914

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: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VCP: PM2, PM5, PS4:Moderate, PP1, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	The R159H variant in the VCP gene has been reported previously in association with inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD), as well as both sporadic and familial forms of amyotrophic lateral sclerosis (Haubenberger et al., 2005; Ayaki et al., 2014; van der Zee et al., 2009). In vitro expression studies of the R159H variant in SH-SY5Y cells showed a statistically significant increase in the percentage of cells with cytoplasmic TDP-43; translocation of TDP-43 to the cytoplasm and aggregation in the cytoplasm has previously been reported as a feature of VCP-related ALS (Ayaki et al., 2014). The R159H variant is observed in 1/22300 alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). Although the R159H variant is a conservative amino acid substitution, it occurs in the four-stranded b barrel in the CDC48 domain, a critical functional domain (Hubbers et al., 2007). We interpret R159H as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). It is statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant has been identified in multiple unrelated individuals with clinical features of FTD/ALS as well as IBMPFD. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMIDs: 22270372, 27226613, 25492614) The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2024	PP1, PP2, PS3, PS4 -

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

VCP-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 04, 2024

The VCP c.476G>A variant is predicted to result in the amino acid substitution p.Arg159His. This variant is reported to be causative for progressive proximal myopathy and Paget disease of the bone in four affected members of an Australian family (Haubenberger et al. 2005. PubMed ID: 16247064). It was also reported to be causative for inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) (van der Zee et al. 2009. PubMed ID: 19704082). In vitro functional studies in HEK293T and SH-SY5Y cells have demonstrated that expression of this variant results in TDP-43 mislocalization (Figure 6, Ayaki et al. 2014. PubMed ID: 25492614). The c.476G>A variant has also been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/8474/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jan 23, 2023

- -

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

Jan 25, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 159 of the VCP protein (p.Arg159His). This variant is present in population databases (rs121909335, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD) (PMID: 16247064, 19225410, 19704082, 22078486, 24829604, 26555887). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8474). 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: 22270372, 25492614, 26555887, 27226613). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.095	T;T;T
Sift4G	Benign	0.15	T;.;.
Polyphen		0.52	P;.;.
Vest4		0.69
MutPred		0.61		Loss of MoRF binding (P = 0.0208);.;.;
MVP		0.96
MPC		1.7
ClinPred		0.90	D
GERP RS		6.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.80
gMVP		0.87

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: rs121909335; hg19: chr9-35065348;