chr10-74070743-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_014000.3(VCL):c.313C>T(p.Arg105*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 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
Consequence
NM_014000.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251322Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135826
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg105X v ariant in VCL has not been identified in individuals with cardiomyopathy, but ha s been identified in 3/246076 total chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517239). This nonsense variant leads to a premature termination codon at position 105, which is predict ed to lead to a truncated or absent protein. Animal models have shown that loss of function (LOF) of the VCL gene can impact cardiac function resulting in pheno types ranging from arrhythmia to cardiomyopathy (Zemljic-Harpf 2004; Zemljic-Har pf 2007). In summary, while there is some suspicion that LOF variants may contri bute to cardiomyopathy, the clinical significance of the p.Arg105X variant is un certain. ACMG/AMP Criteria applied: PVS1_Moderate; PM2. -
Cardiomyopathy Uncertain:1
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Dilated cardiomyopathy 1W Uncertain:1
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. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in VCL cause disease. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 45606). This variant is present in population databases (rs397517239, ExAC 0.001%). This sequence change creates a premature translational stop signal (p.Arg105*) in the VCL gene. It is expected to result in an absent or disrupted protein product. -
Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at