rs71579353

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_014000.3(VCL):c.829C>A(p.Leu277Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L277L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

VCL
NM_014000.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:1

Conservation

PhyloP100: 2.41

Variant links:

Genes affected

VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

VCL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, VCL

BP4

Computational evidence support a benign effect (MetaRNN=0.09801397).

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3 linkuse as main transcript	c.829C>A	p.Leu277Met	missense_variant	7/22	ENST00000211998.10
VCL	NM_003373.4 linkuse as main transcript	c.829C>A	p.Leu277Met	missense_variant	7/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10 linkuse as main transcript	c.829C>A	p.Leu277Met	missense_variant	7/22	1	NM_014000.3		P18206-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251460

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000937

AC:

137

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000105

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 15

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 07, 2006

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 23, 2021

- -

Dilated cardiomyopathy 1W

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2022

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 277 of the VCL protein (p.Leu277Met). This variant is present in population databases (rs71579353, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 16712796, 24503780, 27930701, 31513939). ClinVar contains an entry for this variant (Variation ID: 12198). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Primary familial dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24503780, 25179549, 28218286, 24062880, 17097056, 27957775, 27930701, 31513939, 29875424, 16712796) -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Oct 31, 2018

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The p.L277M variant (also known as c.829C>A), located in coding exon 7 of the VCL gene, results from a C to A substitution at nucleotide position 829. The leucine at codon 277 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) and sudden cardiac death (Vasile VC et al. Biochem. Biophys. Res. Commun., 2006 Jul;345:998-1003; Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). However, this variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Sep 06, 2022

Variant summary: VCL c.829C>A (p.Leu277Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251860 control chromosomes. The observed variant frequency is approximately 4.3 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 benign. c.829C>A has been reported in the literature in at-least one individual with hypertrophic cardiomyopathy (HCM) and continues to be reported as a VUS in settings of multigene panel testing among cohorts of affected individuals with dilated cardiomyopathy (DCM), sudden cardiac death (SCD) and HCM (example, Vasile_2006, Pugh_2014, Sanchez_2016, Mazzarotto_2019, Robyns_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.55

DEOGEN2

Benign

0.091

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.0026

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.68

N;N

MutationTaster

Benign

0.62

A;A;A

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.37

N;N

REVEL

Benign

0.27

Sift

Benign

0.80

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.0

B;B

Vest4

0.29

MVP

0.67

MPC

0.39

ClinPred

0.011

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.18

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over