ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.3476G>A (p.Arg1159Gln) (rs141199483)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000418627 SCV000928107 uncertain significance not provided 2018-12-09 criteria provided, single submitter clinical testing
GeneDx RCV000418627 SCV000513069 uncertain significance not provided 2018-07-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the FLNC gene. The R1159Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 14/111556 (0.013%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The R1159Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000812023 SCV000952321 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1159 of the FLNC protein (p.Arg1159Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs141199483, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with FLNC-related disease. ClinVar contains an entry for this variant (Variation ID: 377889). 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: "Tolerated"; 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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