ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.5791C>T (p.Arg1931Cys) (rs562155863)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519642 SCV000621821 uncertain significance not provided 2018-06-13 criteria provided, single submitter clinical testing The R1931C variant in the FLNC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1931C variant is observed in 9/126,690 (0.007%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The R1931C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1931C as a variant of uncertain significance.
Invitae RCV000649148 SCV000770973 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2017-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1931 of the FLNC protein (p.Arg1931Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs562155863, ExAC 0.01%). This variant has not been reported in the literature in individuals with FLNC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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