rs150595117

chr10-74114203-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_014000.3(VCL):c.2969C>T(p.Ala990Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VCL
• BP4: Computational evidence support a benign effect (MetaRNN=0.37940946).
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.2969C>T	p.Ala990Val	missense_variant	20/22	ENST00000211998.10
VCL	NM_003373.4	c.2765C>T	p.Ala922Val	missense_variant	19/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.2969C>T	p.Ala990Val	missense_variant	20/22	1	NM_014000.3
VCL	ENST00000372755.7	c.2765C>T	p.Ala922Val	missense_variant	19/21	1		P1
VCL	ENST00000623461.3	n.5568C>T		non_coding_transcript_exon_variant	21/23	1
VCL	ENST00000624354.3	c.*2724C>T		3_prime_UTR_variant, NMD_transcript_variant	19/21	2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152088 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000303 AC: 76 AN: 251016 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135652

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: 0.000278

Gnomad NFE exome AF: 0.000582

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000304 AC: 445 AN: 1461466 Hom.: 0 Cov.: 36 AF XY: 0.000279 AC XY: 203 AN XY: 727040

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152088 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000340 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1W Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, null variants have been reported in patients and therefore loss-of-function is speculated (PMID: 32516855). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic carriers have been reported in families with null variants (PMID: 32516855). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to alaine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (82 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated C-terminal tail region (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified multiple times as a VUS (ClinVar; PMIDs: 25332820, 24503780, 30847666, 33302605). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 990 of the VCL protein (p.Ala990Val). This variant is present in population databases (rs150595117, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of VCL-related conditions (PMID: 24503780, 25332820, 30847666, 31737537). ClinVar contains an entry for this variant (Variation ID: 45603). 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 provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 26, 2017	The variant has been seen in one patient with idiopathic DCM at our center. Testing was performed at Invitae. Given the weak case data, weak segregation data, and higher frequency in population databases than expected, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in 1 case of DCM and 1 case of chemotherapy-induced cardiomyopathy (aACM). The patient with DCM had a different likely pathogenic variant. There is weak case data. There is weak segregation data provided in the chemotherapy-induced cardiomyopathy family. Pugh et al (2014) reported this variant in a 2yo with DCM. The patient also harbored a truncating variant in TTN, which was called likely pathogenic (by LMM at time of publication). Wasielewski et al (2014) reported the variant in a patient with anthracycline-associated cardiomyopathy. The text of the paper reports that it segregates with disease in the family, but the pedigree provided is only a two generation pedigree and the only relatives tested were four sisters. The sisters had either aACM, DCM or SCICD. In silico analyses do not agree on the potential impact of this variant on protein function. It should be noted that all of the disease-causing variants in ClinVar are loss of function variants. However, the ExAC variation constraints do show that the VCL gene has fewer missense variants than would be expected by chance. The variant is present in 83 of 138,352 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant has been seen in 72 of 63,142 European (Non-finnish individuals) (MAF = 0.057%), 7 of 12,869 Finnish individuals (MAF - 0.027%) The average coverage at that site in gnomAD is 84x for exomes and 30x for genomes. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2022	Reported in association with cardiomyopathy; however, several patients also harbor additional potentially disaese-causing cardiogenetic variants and this variant did not segregate with disease in several affected members of one family (Wasielewski et al., 2014; Pugh et al., 2014; van Lint et al., 2019; Marschall et al., 2019; Fernlund et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24503780, 33302605, 31737537, 30847666, 25332820, 30615648) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 30, 2012

The Ala990Val variant in VCL has been identified in 4/8600 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS, dbSNP rs150595117). Computational analyses (biochemica l amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not pr ovide strong support for or against an impact to the protein. Additional informa tion is needed to fully assess the clinical significance of this variant. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 14, 2020

- -

Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 25, 2023

The p.A990V variant (also known as c.2969C>T), located in coding exon 20 of the VCL gene, results from a C to T substitution at nucleotide position 2969. The alanine at codon 990 is replaced by valine, an amino acid with some similar properties. In one family, this variant was described among three sisters, two of whom had anthracycline-associated cardiomyopathy related to systemic cancer therapy while the third had mild dilated cardiomyopathy (DCM) (Wasielewski M et al. Open Heart, 2014;1:e000116). This variant has also been reported in unrelated individuals with DCM and hypertrophic cardiomyopathy (HCM); however, clinical details were limited, and additional cardiac variants were detected in some cases (Pugh TJ et al. Genet Med. 2014;16(8):601-8; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Fernlund E et al. Genes (Basel), 2020 12;11:[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.36
Sift	Benign	0.074	T;D
Sift4G	Benign	0.077	T;T
Polyphen		1.0	D;P
Vest4		0.69
MVP		0.58
MPC		2.5
ClinPred		0.34	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.59
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs150595117; hg19: chr10-75873961;