chr10-74097316-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_014000.3(VCL):c.1856C>T(p.Ala619Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A619E) has been classified as Uncertain significance.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.1856C>T | p.Ala619Val | missense_variant | 13/22 | ENST00000211998.10 | |
VCL | NM_003373.4 | c.1856C>T | p.Ala619Val | missense_variant | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.1856C>T | p.Ala619Val | missense_variant | 13/22 | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251044Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135680
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461132Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726866
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74346
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1W Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 05, 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 568183). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28611029). This variant is present in population databases (rs771628544, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 619 of the VCL protein (p.Ala619Val). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2022 | The p.A619V variant (also known as c.1856C>T), located in coding exon 13 of the VCL gene, results from a C to T substitution at nucleotide position 1856. The alanine at codon 619 is replaced by valine, an amino acid with similar properties. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohorts; however, clinical details were limited, and additional cardiac variants were detected in some cases. (Haskell GT et al, Circ Cardiovasc Genet. 2017 Jun;10; van Lint FHM et al, Neth Heart J. 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at