rs727505159

Positions:

• chr10-74114804-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_014000.3(VCL):​c.3163C>T​(p.Arg1055*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VCL NM_014000.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.43

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.3163C>T	p.Arg1055*	stop_gained	21/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2959C>T	p.Arg987*	stop_gained	20/21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.3163C>T	p.Arg1055*	stop_gained	21/22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456630 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723960

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 23, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1055X variant in VCL has been previously identified by our laboratory in one individua l with infantile-onset DCM and one individual with possible early signs of DCM. This nonsense variant leads to a premature termination codon at position 1055, w hich is predicted to lead to a truncated or absent protein. Mouse models have sh own that loss of function of the VCL gene leads to cardiac dysfunction, includin g dilated cardiomyopathy (DCM) (Zemljic-Harpf 2007). Heterozygous loss-of-functi on variants in VCL have been identified in several individuals in our laboratory , many of whom had early onset DCM; however, these variants have also been ident ified in unaffected family members and family members with later onset disease ( LMM, unpublished data). In summary, although there is some evidence suggesting a n association between truncating variants in VCL and DCM, there is not currently enough information to determine the strength of this association or to clearly delineate a mode of inheritance. Therefore, this variant is classified as uncert ain significance. ACMG/AMP Criteria applied: PM2 (Richards 2015). -

Dilated cardiomyopathy 1W Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 31, 2023

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. ClinVar contains an entry for this variant (Variation ID: 179831). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 32516855, 32746448). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1055*) in the VCL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VCL cause disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2018

A variant of uncertain significance has been identified in the VCL gene. The R1055X variant has not been published as pathogenic or been reported as benign to our knowledge. The R1055X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, no other nonsense variants in the VCL gene have been reported as definitively disease-causing variants in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). While heterozygous VCL knockout mice (VCL+/-) are viable and lack gross cardiac abnormalities, they appear to be predisposed to cardiac failure when challenged with increased hemodynamic loading, as assessed by transverse aortic constriction (Zemljic-Harpf et al., 2004). Furthermore, cardiomyocyte membrane cortical stiffness was significantly decreased in mice with cardiomyocyte-specific inactivation of one VCL allele, and normal membrane stiffness was rescued when vinculin expression was restored (Tangney et al., 2013). Nevertheless, the role of these phenomena in the development of cardiomyopathy in humans is unclear. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The p.R1055* variant (also known as c.3163C>T), located in coding exon 21 of the VCL gene, results from a C to T substitution at nucleotide position 3163. This changes the amino acid from an arginine to a stop codon within coding exon 21. This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of VCL has not been established as a mechanism of disease. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.95
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs727505159; hg19: chr10-75874562; COSMIC: COSV53008271;