NM_014000.3(VCL):c.1555A>C (p.Ile519Leu) AND not specified

Germline classification:: Benign (2 submissions)
Last evaluated:: Nov 5, 2019
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000038798.11

Allele description [Variation Report for NM_014000.3(VCL):c.1555A>C (p.Ile519Leu)]

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

Gene:

VCL:vinculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q22.2

Genomic location:

Preferred name:

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

Other names:

p.I519L:ATC>CTC

HGVS:

NC_000010.11:g.74095667A>C
NG_008868.1:g.102554A>C
NM_003373.4:c.1555A>C
NM_014000.3:c.1555A>CMANE SELECT
NP_003364.1:p.Ile519Leu
NP_054706.1:p.Ile519Leu
NP_054706.1:p.Ile519Leu
LRG_383t1:c.1555A>C
LRG_383:g.102554A>C
LRG_383p1:p.Ile519Leu
NC_000010.10:g.75855425A>C
NM_014000.2:c.1555A>C
c.1555A>C

Protein change:

I519L

Links:

dbSNP: rs141033098

NCBI 1000 Genomes Browser:

rs141033098

Molecular consequence:

NM_003373.4:c.1555A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_014000.3:c.1555A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000062476	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Benign (Apr 6, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17785437, 23396983, 24033266
SCV000699356	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Nov 5, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23396983, 23861362, 24503780, 26191084 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000062476

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Benign
(Apr 6, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000699356

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Nov 5, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	4	4	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy.

Zemljic-Harpf AE, Miller JC, Henderson SA, Wright AT, Manso AM, Elsherif L, Dalton ND, Thor AK, Perkins GA, McCulloch AD, Ross RS.

Mol Cell Biol. 2007 Nov;27(21):7522-37. Epub 2007 Sep 4.

PubMed [citation]

PMID:: 17785437
PMCID:: PMC2169049

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000062476.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		4	not provided	4	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699356.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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