ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1583G>A (p.Arg528His) (rs746095066)

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Total submissions: 2
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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.
Invitae RCV000802649 SCV000942490 uncertain significance Dilated cardiomyopathy 1W 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 528 of the VCL protein (p.Arg528His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs746095066, ExAC 0.01%). This variant has not been reported in the literature in individuals with VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 202160). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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.

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