VCV000217877.6 - ClinVar

NM_007126.5(VCP):c.271A>T (p.Asn91Tyr)

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.

(4)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007126.5(VCP):c.271A>T (p.Asn91Tyr)

Variation ID: 217877 Accession: VCV000217877.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 35067922 (GRCh38) [ NCBI UCSC ] 9: 35067919 (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	Nov 20, 2015	Feb 28, 2024	Apr 11, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_007126.5:c.271A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009057.1:p.Asn91Tyr	missense
NM_001354927.2:c.136A>T	NP_001341856.1:p.Asn46Tyr	missense
NM_001354928.2:c.136A>T	NP_001341857.1:p.Asn46Tyr	missense
NC_000009.12:g.35067922T>A
NC_000009.11:g.35067919T>A
NG_007887.1:g.9821A>T
LRG_657:g.9821A>T

... more HGVS ... less HGVS

Protein change

N91Y, N46Y

Other names

Canonical SPDI

NC_000009.12:35067921:T:A

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.

Links

ClinGen: CA279635 OMIM: 601023.0012 dbSNP: rs863225291 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	614	700

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	Likely pathogenic (1)	no assertion criteria provided	Sep 16, 2014	RCV000201935.1
INCLUSION BODY MYOPATHY WITHOUT EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1	Pathogenic (1)	no assertion criteria provided	Dec 23, 2020	RCV001271081.2
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6	Pathogenic (1)	no assertion criteria provided	Dec 23, 2020	RCV001271088.1
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	Apr 11, 2022	RCV002519583.3

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 (Apr 11, 2022)	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: SCV003441338.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 27538664 Comment: This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 91 of the VCP protein (p.Asn91Tyr). … (more) This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 91 of the VCP protein (p.Asn91Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with VCP-related conditions (PMID: 27538664; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217877). 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. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Sep 16, 2014)	no assertion criteria provided Method: clinical testing	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia type 1 Affected status: yes Allele origin: germline	Mendelics Accession: SCV000256873.1 First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015	Publications: PubMed (2) PubMed: 15034582‚ 19704082
Pathogenic (Dec 23, 2020)	no assertion criteria provided Method: literature only	INCLUSION BODY MYOPATHY WITHOUT EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001451902.1 First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020	Publications: PubMed (1) PubMed: 27538664 Comment on evidence: In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous c.271A-T transversion in … (more) In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous c.271A-T transversion in exon 3 of the VCP gene, resulting in an asn91-to-tyr (N91Y) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of inclusion body myopathy (IBMPFD1; 167320), but he had no signs of Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant amyotrophic lateral sclerosis (FTDALS6; 613954) without signs of Paget disease or frontotemporal dementia. Their father presented at age 66 with behavioral variant frontotemporal dementia (613954) without signs of Paget disease, myopathy, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. (less)
Pathogenic (Dec 23, 2020)	no assertion criteria provided Method: literature only	FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001451910.1 First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020	Publications: PubMed (1) PubMed: 27538664 Comment on evidence: In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous c.271A-T transversion in … (more) In 2 Brazilian brothers and their father with different clinical manifestations of VCP-related neurologic disease, Abrahao et al. (2016) identified a heterozygous c.271A-T transversion in exon 3 of the VCP gene, resulting in an asn91-to-tyr (N91Y) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with a neurologic phenotype in the family. The variant was not present in the Exome Variant Server or ExAC databases, or in 1000 control Brazilian exomes. Functional studies of the variant were not performed, but it was predicted to be pathogenic. The proband presented in his forties with proximal muscle weakness associated with dystrophic features, myofibrillar disorganization, and rimmed vacuoles on muscle biopsy, consistent with a diagnosis of inclusion body myopathy (IBMPFD1; 167320), but he had no signs of Paget disease or dementia. His affected brother presented in his late thirties with lower motor neuron-predominant amyotrophic lateral sclerosis (FTDALS6; 613954) without signs of Paget disease or frontotemporal dementia. Their father presented at age 66 with behavioral variant frontotemporal dementia (613954) without signs of Paget disease, myopathy, or ALS. The findings emphasized the extreme phenotypic variability associated with VCP mutations, even within the same family. (less)

Comment:

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 91 of the VCP protein (p.Asn91Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with VCP-related conditions (PMID: 27538664; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217877). 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. For these reasons, this variant has been classified as Pathogenic.

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
One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia.	Abrahao A	Journal of the neurological sciences	2016	PMID: 27538664
Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His.	van der Zee J	Neurology	2009	PMID: 19704082
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

Text-mined citations for rs863225291 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_007126.5(VCP):c.271A>T (p.Asn91Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs863225291 ...