rs876657674

Positions:

• chr10-74074789-A-AG

Variant summary

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

The NM_014000.3(VCL):​c.670dup​(p.Glu224GlyfsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCL NM_014000.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

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	UniProt
VCL	NM_014000.3	c.670dup	p.Glu224GlyfsTer17	frameshift_variant	6/22	ENST00000211998.10
VCL	NM_003373.4	c.670dup	p.Glu224GlyfsTer17	frameshift_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.670dup	p.Glu224GlyfsTer17	frameshift_variant	6/22	1	NM_014000.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 06, 2022

The p.Glu224GlyfsX17 variant in VCL has been identified in an infant with dilated cardiomyopathy (DCM; Hawley 2020 PMID: 32516855, LMM data) and was absent from large population studies. This frameshift variant leads to a premature termination codon beginning at position 224 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Mouse models have shown that loss of function of the VCL gene leads to cardiac dysfunction, including DCM (Zemljic-Harpf 2007 PMID:17785437). Heterozygous loss-of-function 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 identified in unaffected family members and family members with later onset disease (Hawley 2020 PMID: 32516855). In summary, although there is some evidence suggesting an 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 uncertain significance. ACMG/AMP Criteria applied: PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

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: rs876657674; hg19: chr10-75834547;