ClinVar Miner

Submissions for variant NM_014000.3(VCL):c.1583G>A (p.Arg528His)

gnomAD frequency: 0.00005  dbSNP: rs746095066
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183999 SCV000236493 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the VCL gene. The R528H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/277220 (0.003%) alleles in large population cohorts (Lek et al., 2016). The R528H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In short, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000802649 SCV000942490 uncertain significance Dilated cardiomyopathy 1W 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the VCL protein (p.Arg528His). This variant is present in population databases (rs746095066, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with VCL-related conditions. ClinVar contains an entry for this variant (Variation ID: 202160). 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.
Ambry Genetics RCV002399684 SCV002708305 uncertain significance Cardiovascular phenotype 2021-11-24 criteria provided, single submitter clinical testing The p.R528H variant (also known as c.1583G>A), located in coding exon 12 of the VCL gene, results from a G to A substitution at nucleotide position 1583. The arginine at codon 528 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Fulgent Genetics, Fulgent Genetics RCV002503722 SCV002815349 uncertain significance Dilated cardiomyopathy 1W; Hypertrophic cardiomyopathy 15 2021-10-13 criteria provided, single submitter clinical testing

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