Submissions for variant NM_001458.5(FLNC):c.2425G>A (p.Val809Met)

gnomAD frequency: 0.00005  dbSNP: rs775770671

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001248674	SCV001422179	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 809 of the FLNC protein (p.Val809Met). This variant is present in population databases (rs775770671, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28436997). ClinVar contains an entry for this variant (Variation ID: 972607). 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	RCV002447232	SCV002735203	uncertain significance	Cardiovascular phenotype	2023-11-15	criteria provided, single submitter	clinical testing	The p.V809M variant (also known as c.2425G>A), located in coding exon 16 of the FLNC gene, results from a G to A substitution at nucleotide position 2425. The valine at codon 809 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort (Janin A et al. Clin Genet, 2017 Dec;92:616-623). 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.
Clinical Genetics, Academic Medical Center	RCV001700725	SCV001917238	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001700725	SCV001932336	uncertain significance	not provided		no assertion criteria provided	clinical testing