VCV000008473.49 - ClinVar

NM_007126.5(VCP):c.572G>A (p.Arg191Gln)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007126.5(VCP):c.572G>A (p.Arg191Gln)

Variation ID: 8473 Accession: VCV000008473.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 35065255 (GRCh38) [ NCBI UCSC ] 9: 35065252 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 17, 2016	Oct 26, 2024	Jan 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007126.5:c.572G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009057.1:p.Arg191Gln	missense
NM_001354927.2:c.437G>A	NP_001341856.1:p.Arg146Gln	missense
NM_001354928.2:c.437G>A	NP_001341857.1:p.Arg146Gln	missense
NC_000009.12:g.35065255C>T
NC_000009.11:g.35065252C>T
NG_007887.1:g.12488G>A
LRG_657:g.12488G>A
LRG_657t1:c.572G>A
	P55072:p.Arg191Gln

... more HGVS ... less HGVS

Protein change

R191Q, R146Q

Other names

Canonical SPDI

NC_000009.12:35065254:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA254406 UniProtKB: P55072#VAR_033021 OMIM: 601023.0006 dbSNP: rs121909334 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
VCP		-	-	GRCh38 GRCh37	616	702

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	Pathogenic (2)	criteria provided, single submitter	Apr 30, 2018	RCV000008994.5
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6	Pathogenic/Likely pathogenic (3)	no assertion criteria provided	Jun 1, 2022	RCV000023064.6
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 27, 2020	RCV000516636.40
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Inclusion body myopathy with Paget disease of bone and frontotemporal dementia	Pathogenic (1)	criteria provided, single submitter	Jan 21, 2024	RCV000555373.11
Charcot-Marie-Tooth disease type 2Y Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1	Pathogenic (1)	criteria provided, single submitter	Nov 30, 2021	RCV002496309.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 05, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000708696.2 First in ClinVar: Dec 19, 2017 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VCP Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Dec 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713487.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (13) PubMed: 15034582‚ 19237541‚ 21145000‚ 22270372‚ 21984748‚ 23498975‚ 23333620‚ 22900631‚ 24196964‚ 27226613‚ 28360103‚ 27708273‚ 30279455 Comment: PS3, PS4, PP1 Number of individuals with the variant: 1
Pathogenic (Jul 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020855.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000638349.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 15034582‚ 21145000‚ 21984748‚ 22900631‚ 19237541‚ 22270372‚ 23333620‚ 23498975‚ 24196964‚ 27226613 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the VCP protein (p.Arg191Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the VCP protein (p.Arg191Gln). This variant is present in population databases (rs121909334, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy with Paget‚Äôs disease of the bone and frontotemporal dementia (IBMPFD), facioscapulohumeral muscular dystrophy-like phenotype and amyotrophic lateral sclerosis (PMID: 15034582, 21145000, 21984748, 22900631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8473). 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: 19237541, 22270372, 23333620, 23498975, 24196964, 27226613). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248045.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Apr 30, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inclusion body myopathy with early-onset paget disease and frontotemporal dementia Affected status: yes Allele origin: germline	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000840429.1 First in ClinVar: Sep 17, 2016 Last updated: Sep 17, 2016	Number of individuals with the variant: 1 Age: 50-59 years Sex: male
Likely pathogenic (Feb 27, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000616238.2 First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2021	Publications: PubMed (15) PubMed: 28692196‚ 26105173‚ 15034582‚ 23498975‚ 23333620‚ 19237541‚ 21145000‚ 22270372‚ 21984748‚ 22900631‚ 24196964‚ 27226613‚ 27708273‚ 28360103‚ 30279455 Comment: The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. … (more) The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
Pathogenic (May 15, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001819775.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Published In vitro studies of R191Q expression support a damaging effect on protein function (Gitcho et al., 2009; Ludtmann et al., 2017); Not observed at … (more) Published In vitro studies of R191Q expression support a damaging effect on protein function (Gitcho et al., 2009; Ludtmann et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29789581, 28364293, 27708273, 21145000, 15034582, 21984748, 19364651, 28564594, 28360103, 27226613, 23498975, 22270372, 24196964, 19237541, 23333620, 22900631, 30279455) (less)
Pathogenic (Nov 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Charcot-Marie-Tooth disease type 2Y Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002809874.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Apr 25, 2018)	no assertion criteria provided Method: clinical testing	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Affected status: yes Allele origin: germline	Institute of Human Genetics, Cologne University Accession: SCV000787766.1 First in ClinVar: Sep 17, 2016 Last updated: Sep 17, 2016
Pathogenic (Jan 01, 2012)	no assertion criteria provided Method: literature only	INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029208.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2020	Publications: PubMed (3) PubMed: 15034582‚ 21145000‚ 21984748 Comment on evidence: In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified … (more) In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP gene, resulting in an arg-to-gln substitution at codon 191 (R191Q). Using exome sequencing, Johnson et al. (2010) identified heterozygosity for the R191Q mutation in the VCP gene, which they stated resulted from a 961G-A transition in exon 5, in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954). Affected individuals presented in adulthood with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classical ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. Sacconi et al. (2012) identified a heterozygous R191Q mutation in 2 unrelated men in their fifties who presented with a phenotype consistent with IBMPFD. One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. EMG showed myopathic patterns. One patient was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease. (less)
Pathogenic (Jan 01, 2012)	no assertion criteria provided Method: literature only	FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001451912.1 First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020	Publications: PubMed (3) PubMed: 15034582‚ 21145000‚ 21984748 Comment on evidence: In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified … (more) In 1 of 13 families with autosomal dominant inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD1; 167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP gene, resulting in an arg-to-gln substitution at codon 191 (R191Q). Using exome sequencing, Johnson et al. (2010) identified heterozygosity for the R191Q mutation in the VCP gene, which they stated resulted from a 961G-A transition in exon 5, in 4 affected members of an Italian family with frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6; 613954). Affected individuals presented in adulthood with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classical ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. Sacconi et al. (2012) identified a heterozygous R191Q mutation in 2 unrelated men in their fifties who presented with a phenotype consistent with IBMPFD. One had scapuloperoneal weakness without facial involvement and increased serum creatine kinase. The second patient had facial weakness, shoulder and pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle biopsies of both patients showed mild dystrophic changes, but no inclusion bodies. EMG showed myopathic patterns. One patient was later found to have a mild dysexecutive syndrome, but neither had evidence of Paget disease. (less)
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005091359.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team
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Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 191 of the VCP protein (p.Arg191Gln). This variant is present in population databases (rs121909334, gnomAD 0.004%). This missense change has been observed in individuals with inclusion body myopathy with Paget‚Äôs disease of the bone and frontotemporal dementia (IBMPFD), facioscapulohumeral muscular dystrophy-like phenotype and amyotrophic lateral sclerosis (PMID: 15034582, 21145000, 21984748, 22900631). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8473). 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: 19237541, 22270372, 23333620, 23498975, 24196964, 27226613). For these reasons, this variant has been classified as Pathogenic.

Comment:

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Comment:

Published In vitro studies of R191Q expression support a damaging effect on protein function (Gitcho et al., 2009; Ludtmann et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29789581, 28364293, 27708273, 21145000, 15034582, 21984748, 19364651, 28564594, 28360103, 27226613, 23498975, 22270372, 24196964, 19237541, 23333620, 22900631, 30279455)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.	Koriath C	Molecular psychiatry	2020	PMID: 30279455
Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy.	Al-Obeidi E	Clinical genetics	2018	PMID: 28692196
Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons.	Ludtmann MHR	The Journal of biological chemistry	2017	PMID: 28360103
The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States.	Reddy HM	Journal of human genetics	2017	PMID: 27708273
Pathogenic Mutations in the Valosin-containing Protein/p97(VCP) N-domain Inhibit the SUMOylation of VCP and Lead to Impaired Stress Response.	Wang T	The Journal of biological chemistry	2016	PMID: 27226613
Mutational spectrum and phenotypic variability of VCP-related neurological disease in the UK.	Figueroa-Bonaparte S	Journal of neurology, neurosurgery, and psychiatry	2016	PMID: 26105173
Altered intersubunit communication is the molecular basis for functional defects of pathogenic p97 mutants.	Tang WK	The Journal of biological chemistry	2013	PMID: 24196964
Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels.	Bartolome F	Neuron	2013	PMID: 23498975
A unique IBMPFD-related P97/VCP mutation with differential binding pattern and subcellular localization.	Erzurumlu Y	The international journal of biochemistry & cell biology	2013	PMID: 23333620
Phenotypic variability in three families with valosin-containing protein mutation.	Spina S	European journal of neurology	2013	PMID: 22900631
The role of the N-domain in the ATPase activity of the mammalian AAA ATPase p97/VCP.	Niwa H	The Journal of biological chemistry	2012	PMID: 22270372
Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.	Sacconi S	Journal of medical genetics	2012	PMID: 21984748
Exome sequencing reveals VCP mutations as a cause of familial ALS.	Johnson JO	Neuron	2010	PMID: 21145000
VCP mutations causing frontotemporal lobar degeneration disrupt localization of TDP-43 and induce cell death.	Gitcho MA	The Journal of biological chemistry	2009	PMID: 19237541
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein.	Watts GD	Nature genetics	2004	PMID: 15034582
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VCP	-	-	-	-
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Text-mined citations for rs121909334 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_007126.5(VCP):c.572G>A (p.Arg191Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909334 ...