rs373010557

Positions:

chr10-74107239-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_014000.3(VCL):c.2444A>G(p.Lys815Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

VCL
NM_014000.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 8.95

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 -4 ACMG points.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3 link	c.2444A>G	p.Lys815Arg	missense_variant	17/22	ENST00000211998.10	NP_054706.1	P18206-1V9HWK2B3KXA2
VCL	NM_003373.4 link	c.2444A>G	p.Lys815Arg	missense_variant	17/21		NP_003364.1	P18206-2A0A024QZN4B3KXA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10 link	c.2444A>G	p.Lys815Arg	missense_variant	17/22	1	NM_014000.3	ENSP00000211998.5		P18206-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251466

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000755

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1W

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 815 of the VCL protein (p.Lys815Arg). This variant is present in population databases (rs373010557, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 24062880, 27532257, 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 45596). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 19, 2014

The Lys815Arg variant in VCL has been identified in one individual with DCM who also carried a second variant of unknown significance in MYBPC3 and segregated w ith disease in 3 affected family members, 2 of whom also carried the MYBPC3 vari ant (Wells 2011 and LMM unpublished data). The Lys815Arg variant has been identi fied in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Proje ct (http://evs.gs.washington.edu/EVS; dbSNP rs373010557). Lysine (Lys) at positi on 815 is highly conserved in mammals and evolutionarily distant species, sugges ting that a change at this position may not be tolerated. While VCL variants ha ve been identified in individuals with HCM as well as DCM (Olson 2002, Vasile 20 06), few studies exist and the contribution of VCL to HCM and/or DCM as well as the types of pathogenic variation have not been well established. In summary, th e clinical significance of the Lys815Arg variant is uncertain and additional stu dies are needed to fully establish its clinical significance. -

Dilated cardiomyopathy 1S

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 26, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2021

Reported with an MYBPC3 variant in a proband with DCM and a family history of DCM and bicuspid aortic valve; three affected relatives harbored the VCL variant, two of whom also harbored the MYBPC3 variant (Wells et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 24503780, 24062880, 32880476, 30847666) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.2444A>G (p.K815R) alteration is located in exon 17 (coding exon 17) of the VCL gene. This alteration results from a A to G substitution at nucleotide position 2444, causing the lysine (K) at amino acid position 815 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.9

L;L

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.93

N;N

REVEL

Pathogenic

0.72

Sift

Benign

0.088

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.98

D;B

Vest4

0.67

MVP

0.41

MPC

0.64

ClinPred

0.29

GERP RS

5.6

Varity_R

0.23

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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