Submissions for variant NM_001458.5(FLNC):c.1645A>G (p.Ile549Val)

gnomAD frequency: 0.00009  dbSNP: rs547997371

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480032	SCV000573731	uncertain significance	not provided	2018-09-24	criteria provided, single submitter	clinical testing	The I549V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I549V 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 is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000686907	SCV000814448	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 549 of the FLNC protein (p.Ile549Val). This variant is present in population databases (rs547997371, gnomAD 0.009%), and has an allele count higher than expected for a pathogenic variant. 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: 423964). 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.
Ambry Genetics	RCV002395178	SCV002704010	uncertain significance	Cardiovascular phenotype	2022-12-28	criteria provided, single submitter	clinical testing	The p.I549V variant (also known as c.1645A>G), located in coding exon 10 of the FLNC gene, results from an A to G substitution at nucleotide position 1645. The isoleucine at codon 549 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000480032	SCV003833138	uncertain significance	not provided	2019-09-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003962347	SCV004785732	likely benign	FLNC-related disorder	2023-12-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).