10-74074773-CAA-CAAA

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_014000.3(VCL):​c.659dupA​(p.Asn220LysfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,612,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N220N) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

VCL
NM_014000.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: -0.284
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 10-74074773-C-CA is Pathogenic according to our data. Variant chr10-74074773-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45618.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VCLNM_014000.3 linkc.659dupA p.Asn220LysfsTer21 frameshift_variant Exon 6 of 22 ENST00000211998.10 NP_054706.1 P18206-1V9HWK2B3KXA2
VCLNM_003373.4 linkc.659dupA p.Asn220LysfsTer21 frameshift_variant Exon 6 of 21 NP_003364.1 P18206-2A0A024QZN4B3KXA2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VCLENST00000211998.10 linkc.659dupA p.Asn220LysfsTer21 frameshift_variant Exon 6 of 22 1 NM_014000.3 ENSP00000211998.5 P18206-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151942
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1460894
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
726716
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
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:
0.0000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151942
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74192
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1
Oct 28, 2010
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Asn220fs variant has not been reported in the literature nor been identified in any other family tested by our laboratory. This variant is predicted to caus e a frameshift, which alters the protein's amino acid sequence beginning at codo n 220 and leads to a premature stop codon 20 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In addition, 3 out of 13 VCL variants previously identified in DCM patients are loss of functio n variants (LMM unpublished data). Therefore, the Asn220fs variant is likely to be pathogenic. -

Dilated cardiomyopathy 1W Uncertain:1
Dec 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn220Lysfs*21) 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. This variant is present in population databases (rs770713697, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of VCL-related conditions (PMID: 27532257, 30923642, 34495297). ClinVar contains an entry for this variant (Variation ID: 45618). 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. -

Cardiovascular phenotype Uncertain:1
Nov 21, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.659dupA variant, located in coding exon 6 of the VCL gene, results from a duplication of A at nucleotide position 659, causing a translational frameshift with a predicted alternate stop codon (p.N220Kfs*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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517245; hg19: chr10-75834531; API