Submissions for variant NM_001458.5(FLNC):c.6877C>T (p.Arg2293Cys)

gnomAD frequency: 0.00001  dbSNP: rs571239463

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001299875	SCV001488991	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-07-28	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 2293 of the FLNC protein (p.Arg2293Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32112656). ClinVar contains an entry for this variant (Variation ID: 1003336). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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	RCV002366132	SCV002666109	uncertain significance	Cardiovascular phenotype	2019-05-11	criteria provided, single submitter	clinical testing	The p.R2293C variant (also known as c.6877C>T), located in coding exon 41 of the FLNC gene, results from a C to T substitution at nucleotide position 6877. The arginine at codon 2293 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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.
Clinical Genetics, Academic Medical Center	RCV001729843	SCV001979164	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001729843	SCV001979577	uncertain significance	not provided		no assertion criteria provided	clinical testing