rs150385900

Positions:

• chr10-74107316-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_014000.3(VCL):​c.2521G>C​(p.Asp841His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 9.60

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VCL. . Gene score misZ 2.7082 (greater than the threshold 3.09). Trascript score misZ 4.2375 (greater than threshold 3.09). GenCC has associacion of gene with dilated cardiomyopathy, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1W.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008257151).
• BP6: Variant 10-74107316-G-C is Benign according to our data. Variant chr10-74107316-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 192106.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr10-74107316-G-C is described in Lovd as [Benign]. Variant chr10-74107316-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000617 (94/152306) while in subpopulation EAS AF= 0.0152 (79/5190). AF 95% confidence interval is 0.0125. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.2521G>C	p.Asp841His	missense_variant	17/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2521G>C	p.Asp841His	missense_variant	17/21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2521G>C	p.Asp841His	missense_variant	17/22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00115 AC: 288 AN: 251438 Hom.: 1 AF XY: 0.00106 AC XY: 144 AN XY: 135902

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0147

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000312 AC: 456 AN: 1461894 Hom.: 1 Cov.: 34 AF XY: 0.000289 AC XY: 210 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00877

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74478

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0152

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000502

ExAC AF: 0.000988 AC: 120

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 20, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. VCL (vinculin) is a component of Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. It regulates cell-surface E-cadherin expression and potentiates mechanosensing by the E-cadherin complex. May also play important roles in cell morphology and locomotion. Loss of VCL mediated protein have been previously reported in association with cardiomyopathy. Maeda et al (1997) demonstrated a deficiency of cardiac metavinculin mRNA and protein in a subject with idiopathic dilated cardiomyopathy. This cytoskeletal defect was associated with abnormalities in ventricular function, cardiac dilatation, and immunohistological defects at the site of metavinculin absence: the cardiomyocyte membrane and intercalated disk. PCR of cardiac cDNA detected absence of the metavinculin transcript in cardiac tissue. PCR of genomic DNA showed that the metavinculin exon was present but not utilized in the cardiac transcript. The molecular defect appears to affect splicing of the metavinculin exon in cardiac tissue. Olson et al (2002) performed mutational analyses of the metavinculin-specific exon of VCL in 350 unrelated patients with DCM. One missense mutation (Arg975Trp) and one 3-bp deletion (Leu954del) were identified. These mutations involved conserved amino acids, were absent in 500 control individuals, and significantly altered metavinculin-mediated cross-linking of actin filaments in an in vitro assay. Vasile et al (2005) performed mutational analysis of VCL, exon 19 only on a cohort of 389 unrelated patients with clinical HCM, previously genotyped for the 8 most common HCM-associated myofilament-encoding genes. Overall, 3 nonsynonymous single nucleotide polymorphisms (A934V, P943A, and R975W) were detected in 4 patients. R975 is a highly conserved residue and R975W was absent in over 1400 reference alleles. R975W is shown in 1 individual of 6,500 people in the NHLBI database. No mouse-model data and no segregation data is available. The background probability of carrying a missense variant in VCL is approximately 1.7% (NHLBI cohort as of 4/23/13). While VCL may be a candidate gene for pre-disposition for cardiomyopathy, there is insufficient evidence at this time to suggest that any variant in VCL is sufficient enough to cause disease. This variant is novel. Asp841His results in a non-conservative amino acid substitution of a negative changed Aspartic acid with a positively charged Histidine at a position that is class conserved. In silico analysis predicts possibly damaging (Polyphen score of 0.46) and is predicted disease causing by Mutation Taster (score 81) and SIFT (0.05). This variant is not reported in dbSNP and 1000 genomes. The variant is not currently listed in NHLBI Exome Sequencng Project dataset, which included variant call on ~6,500 Caucasian and African American individuals (as of 4/22/13). Note this dataset does not match the patient's ancestry. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 01, 2015	p.Asp841His in exon 17 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (114/8626) of East Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150385900). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2019	This variant is associated with the following publications: (PMID: 28373245, 23861362) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2016	Variant summary: The VCL c.2521G>C (p.Asp841His) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is not located in any known domain (InterPro, UniProt). This variant was found in 120/121210 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0132159 (114/8626). No homozygotes have been detected in general population. This frequency is about 529 times the estimated maximal expected allele frequency of a pathogenic VCL variant (0.000025), strong evidence that this is likely a benign polymorphism found primarily in the populations of East Asian origin. One of three clinical diagnostic laboratories has classified this variant as benign based on ExAC population frequency, while two other labs classify the variant as a VUS, likely due to the large ExAC database not being utalized at the time of evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and there are no published functional studies for the variant. Taken together, this variant is classified as Benign. -

Dilated cardiomyopathy 1W Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 13, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.93	P;B
Vest4		0.64
MVP		0.17
MPC		1.2
ClinPred		0.089	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.67

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: rs150385900; hg19: chr10-75867074; COSMIC: COSV53011703; COSMIC: COSV53011703;