Submissions for variant NM_001458.5(FLNC):c.4069G>A (p.Gly1357Arg)

gnomAD frequency: 0.00001  dbSNP: rs1218299104

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000810393	SCV000950590	likely pathogenic	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1357 of the FLNC protein (p.Gly1357Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of dilated cardiomyopathy (PMID: 36286284; Invitae). ClinVar contains an entry for this variant (Variation ID: 654428). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001556052	SCV001777564	uncertain significance	not provided	2021-02-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 654428; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV002325579	SCV002627249	uncertain significance	Cardiovascular phenotype	2023-12-20	criteria provided, single submitter	clinical testing	The p.G1357R variant (also known as c.4069G>A), located in coding exon 23 of the FLNC gene, results from a G to A substitution at nucleotide position 4069. The glycine at codon 1357 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in a pediatric proband with dilated cardiomyopathy (DCM), hypertrabeculation, heart failure, and skeletal muscle features. This variant was also detected in the proband's father with cardiac hypertrophy (Baban A et al. J Cardiovasc Dev Dis. 2022 Sep;9(10)). This alteration has been observed in additional individuals with a personal history that is consistent with DCM (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. 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.
Revvity Omics, Revvity	RCV001556052	SCV003831460	uncertain significance	not provided	2021-10-13	criteria provided, single submitter	clinical testing