Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001373768 | SCV001570500 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2021-08-26 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with tryptophan at codon 755 of the FLNC protein (p.Arg755Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 | RCV002447494 | SCV002733406 | uncertain significance | Cardiovascular phenotype | 2022-09-27 | criteria provided, single submitter | clinical testing | The p.R755W variant (also known as c.2263C>T), located in coding exon 14 of the FLNC gene, results from a C to T substitution at nucleotide position 2263. The arginine at codon 755 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in a frontotemporal dementia control cohort (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68). 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. |
| Genetics and Molecular Pathology, |
RCV003447594 | SCV004175464 | uncertain significance | Primary dilated cardiomyopathy | 2023-03-23 | criteria provided, single submitter | clinical testing | The FLNC c.2263C>T variant is classified as VUS (PM2, PP3) The FLNC c.2263C>T variant is a single nucleotide change in exon 14/48 of the FLNC gene, which is predicted to change the amino acid arginine at position 755 in the protein to tryptophan. The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152224 sequenced alleles) (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs990718751), is reported as uncertain significance in individuals with a cardiovascular phenotype by other diagnostic laboratories (ClinVar #1063882) and is not reported in HGMD. This variant has been reported in the literature in an individual with FrontoTemporal Dementia (PMID#26555887). |