ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.4420C>T (p.Arg1474Trp) (rs372454458)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522249 SCV000621851 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing The R1474W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1474W variant is observed in 1/9,826 (0.01%) alleles from individuals of Ashkenazi Jewish background (Lek et al., 2016). This 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 that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000705455 SCV000834453 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1474 of the FLNC protein (p.Arg1474Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs372454458, ExAC 0.01%). This variant has not been reported in the literature in individuals with FLNC-related disease. ClinVar contains an entry for this variant (Variation ID: 452999). 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: "Possibly 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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