ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.6200G>A (p.Arg2067His) (rs776520014)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522328 SCV000619026 uncertain significance not provided 2018-01-25 criteria provided, single submitter clinical testing The R2067H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2067H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000852301 SCV000928321 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4 2019-06-19 criteria provided, single submitter clinical testing A heterozygous variant c.6200G>A (p.Arg2067His) in exon 37 has been observed in FLNC gene. The proband born of a non-consanguineous marriage, presented with clinical indications of myopathy, ataxia, muscle incoordination and decreased power in lower limbs. The patient was observed with the said variant in an autosomal dominant mode of inheritance. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.0008% and 0.005% in the ExAC. The in-silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. In summary, the said variant meets our criteria to be classified as variant of uncertain significance based on the mode of inheritance, in silico prediction and allele frequency in population databases.
Invitae RCV000823001 SCV000963835 uncertain significance Myofibrillar myopathy, filamin C-related; Myopathy, distal, 4; Cardiomyopathy, familial hypertrophic, 26; Dilated Cardiomyopathy, Dominant 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2067 of the FLNC protein (p.Arg2067His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs776520014, ExAC 0.006%). This variant has not been reported in the literature in individuals with FLNC-related disease. ClinVar contains an entry for this variant (Variation ID: 450439). 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: "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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