rs139312390
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_014000.3(VCL):c.688C>T(p.Arg230Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,614,008 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 (★★).
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251292Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135818
GnomAD4 exome AF: 0.000220 AC: 321AN: 1461804Hom.: 0 Cov.: 31 AF XY: 0.000208 AC XY: 151AN XY: 727200
GnomAD4 genome AF: 0.000105 AC: 16AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74410
ClinVar
Submissions by phenotype
not provided Uncertain:5
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Reported in association with DCM; however, specific clinical information was not provided (Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31983221) -
not specified Uncertain:1
The Arg230Cys variant in VCL has been identified in one individual with HCM by o ur laboratory, but did not segregate with disease in one affected relative. It h as been identified in 3/8600 European American chromosomes from a broad populati on by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSN P rs139312390); however, this frequency is too low to rule out a role in disease . Computational analyses (conservation, biochemical amino acid properties, Align GVGD, and SIFT) suggest that this variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, addit ional information is needed to fully assess the clinical significance of this va riant. -
Dilated cardiomyopathy 1W Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 230 of the VCL protein (p.Arg230Cys). This variant is present in population databases (rs139312390, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221). ClinVar contains an entry for this variant (Variation ID: 45620). 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. 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. -
Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The c.688C>T (p.R230C) alteration is located in exon 6 (coding exon 6) of the VCL gene. This alteration results from a C to T substitution at nucleotide position 688, causing the arginine (R) at amino acid position 230 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at