VCV000045582.46 - ClinVar

NM_014000.3(VCL):c.1555A>C (p.Ile519Leu)

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.

(17)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(3); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014000.3(VCL):c.1555A>C (p.Ile519Leu)

Variation ID: 45582 Accession: VCV000045582.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q22.2 10: 74095667 (GRCh38) [ NCBI UCSC ] 10: 75855425 (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	Feb 6, 2015	Oct 8, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_014000.3:c.1555A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_054706.1:p.Ile519Leu	missense
NM_003373.4:c.1555A>C	NP_003364.1:p.Ile519Leu	missense
NC_000010.11:g.74095667A>C
NC_000010.10:g.75855425A>C
NG_008868.1:g.102554A>C
LRG_383:g.102554A>C
LRG_383t1:c.1555A>C	LRG_383p1:p.Ile519Leu

... more HGVS ... less HGVS

Protein change

I519L

Other names

p.I519L:ATC>CTC

Canonical SPDI

NC_000010.11:74095666:A:C

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.00020 (C)

Allele frequency

The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00064

Trans-Omics for Precision Medicine (TOPMed) 0.00070

Exome Aggregation Consortium (ExAC) 0.00072

The Genome Aggregation Database (gnomAD), exomes 0.00072

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00115

Links

ClinGen: CA136703

dbSNP: rs141033098

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.
VCL		-	-	GRCh38 GRCh37	1308	1383

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.
not specified	Benign (2)	criteria provided, multiple submitters, no conflicts	Nov 5, 2019	RCV000038798.11
Cardiomyopathy	Benign (2)	criteria provided, single submitter	Feb 19, 2020	RCV000157581.6
not provided	Conflicting interpretations of pathogenicity (8)	criteria provided, conflicting classifications	Oct 1, 2023	RCV000172735.26
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Nov 8, 2018	RCV000253868.4
Primary familial dilated cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Mar 30, 2017	RCV000624752.3
Ventricular tachycardia	Likely benign (1)	criteria provided, single submitter	May 14, 2019	RCV000852616.1
Dilated cardiomyopathy 1W	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 29, 2024	RCV001081141.14

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.
Uncertain significance (Mar 30, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary familial dilated cardiomyopathy Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740397.1 First in ClinVar: Apr 15, 2018 Last updated: Apr 15, 2018
Uncertain significance (Apr 14, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000707823.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VCL Number of individuals with the variant: 1 Sex: mixed
Benign (Apr 06, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062476.6 First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019	Publications: PubMed (2) PubMed: 17785437‚ 23396983 Comment: The p.Ile519Leu variant in VCL is classified as benign because it has been ident ified in 0.1% (151/126708) of European chromosomes by the Genome Aggreagation … (more) The p.Ile519Leu variant in VCL is classified as benign because it has been ident ified in 0.1% (151/126708) of European chromosomes by the Genome Aggreagation Da tabase (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs141033098). ACMG/AMP Criteria applied: BA1. (less) Number of individuals with the variant: 4
Benign (Nov 05, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699356.2 First in ClinVar: Jun 08, 2015 Last updated: Jun 22, 2020	Publications: PubMed (4) PubMed: 23396983‚ 23861362‚ 24503780‚ 26191084 Comment: Variant summary: VCL c.1555A>C (p.Ile519Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more) Variant summary: VCL c.1555A>C (p.Ile519Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 253200 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 48 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant has been reported in the literature, without strong evidence for causality (Lopes_2013, Pugh_2014), and in one case was reported to co-occur with a truncating DSC2 variant and an in-frame deletion in MYBPC3 (Lopes_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=5) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (May 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ventricular tachycardia Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995319.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1W Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001263795.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 23396983‚ 26191084 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Jul 23, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236469.12 First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018	Comment: This variant is associated with the following publications: (PMID: 26191084, 23396983)
Benign (Feb 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333793.2 First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021
Likely benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1W Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000559720.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Likely benign (Nov 08, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000320414.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Not provided Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051509.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 5
Likely benign (Oct 01, 2023)	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: SCV004126794.9 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: VCL: BS1 Number of individuals with the variant: 1
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917224.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Uncertain significance (Oct 28, 2014)	no assertion criteria provided Method: clinical testing	Cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207327.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Number of individuals with the variant: 1
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928881.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957241.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740308.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
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Comment:

The p.Ile519Leu variant in VCL is classified as benign because it has been ident ified in 0.1% (151/126708) of European chromosomes by the Genome Aggreagation Da tabase (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs141033098). ACMG/AMP Criteria applied: BA1.

Comment:

Variant summary: VCL c.1555A>C (p.Ile519Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00073 in 253200 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 48 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant has been reported in the literature, without strong evidence for causality (Lopes_2013, Pugh_2014), and in one case was reported to co-occur with a truncating DSC2 variant and an in-frame deletion in MYBPC3 (Lopes_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=5) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
BALL-SNP: combining genetic and structural information to identify candidate non-synonymous single nucleotide polymorphisms.	Mueller SC	Genome medicine	2015	PMID: 26191084
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.	Pugh TJ	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24503780
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.	Lopes LR	Journal of medical genetics	2013	PMID: 23396983
Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.	Zemljic-Harpf AE	Molecular and cellular biology	2007	PMID: 17785437
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=VCL	-	-	-	-

Text-mined citations for rs141033098 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_014000.3(VCL):c.1555A>C (p.Ile519Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs141033098 ...