Submissions for variant NM_001458.5(FLNC):c.1468C>T (p.Arg490Cys)

gnomAD frequency: 0.00001  dbSNP: rs1422233407

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001990880	SCV002264419	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 490 of the FLNC protein (p.Arg490Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 1479172). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNC protein function. 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.
Molecular Genetics, Royal Melbourne Hospital	RCV002221295	SCV002498634	uncertain significance	Primary dilated cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in FLNC is predicted to replace arginine with cysteine at codon 490, p.(Arg490Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the ROD1 Ig-like 3 domain. There is a large physicochemical difference between arginine and cysteine. This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with FLNC-related disorders. Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3.
Ambry Genetics	RCV002388974	SCV002697490	uncertain significance	Cardiovascular phenotype	2022-04-11	criteria provided, single submitter	clinical testing	The p.R490C variant (also known as c.1468C>T), located in coding exon 9 of the FLNC gene, results from a C to T substitution at nucleotide position 1468. The arginine at codon 490 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150474	SCV003837890	uncertain significance	Cardiomyopathy	2021-11-29	criteria provided, single submitter	clinical testing