Submissions for variant NM_001458.5(FLNC):c.4700G>T (p.Arg1567Leu)

dbSNP: rs2291569

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492930	SCV000583285	uncertain significance	not provided	2017-05-26	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FLNC gene. The R1567L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1567L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1567L 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000824615	SCV000965520	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2018-07-15	criteria provided, single submitter	clinical testing	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. 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 C15"). This variant has not been reported in the literature in individuals with FLNC-related disease. ClinVar contains an entry for this variant (Variation ID: 430477). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 1567 of the FLNC protein (p.Arg1567Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine.