rs1554668805

Variant names:

• chr9-35065349-C-G
• rs1554668805
• NM_007126.5:c.478G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-35065349-C-G
• chr9-35065349-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_007126.5(VCP):​c.478G>C​(p.Ala160Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A160T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCP NM_007126.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.77
• Publications: 2 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 13 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 chr9-35065349-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2438516.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 9-35065349-C-G is Pathogenic according to our data. Variant chr9-35065349-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532761.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCP	NM_007126.5	c.478G>C	p.Ala160Pro	missense_variant	Exon 5 of 17	ENST00000358901.11	NP_009057.1
VCP	NM_001354927.2	c.343G>C	p.Ala115Pro	missense_variant	Exon 5 of 17		NP_001341856.1
VCP	NM_001354928.2	c.343G>C	p.Ala115Pro	missense_variant	Exon 5 of 17		NP_001341857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCP	ENST00000358901.11	c.478G>C	p.Ala160Pro	missense_variant	Exon 5 of 17	1	NM_007126.5	ENSP00000351777.6
ENSG00000288699	ENST00000681845.1	n.*576G>C		non_coding_transcript_exon_variant	Exon 5 of 5			ENSP00000505452.1
ENSG00000288699	ENST00000681845.1	n.*576G>C		3_prime_UTR_variant	Exon 5 of 5			ENSP00000505452.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 160 of the VCP protein (p.Ala160Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of VCP-related conditions and/or inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (PMID: 28692196, 29754758; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 532761). 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%. This variant disrupts the p.Ala160 amino acid residue in VCP. Other variant(s) that disrupt this residue have been observed in individuals with VCP-related conditions (PMID: 36980948), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 11-27-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T;T
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.95	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.26	T;T;D
Sift4G	Benign	0.40	T;.;.
Polyphen		0.0020	B;.;.
Vest4		0.86
MutPred		0.43		Loss of sheet (P = 0.0315);.;.;
MVP		0.98
MPC		1.7
ClinPred		0.90	D
GERP RS		6.1
PromoterAI		0.0080	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.86
gMVP		0.98
Mutation Taster		=13/87	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: rs1554668805; hg19: chr9-35065346;