Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000649166 | SCV000770991 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-04-03 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2133 of the FLNC protein (p.Arg2133Cys). 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. This variant disrupts the p.Arg2133 amino acid residue in FLNC. Other variant(s) that disrupt this residue have been observed in individuals with FLNC-related conditions (PMID: 25351925, 28356264), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 539432). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30411535). |
| Ambry Genetics | RCV002358861 | SCV002655588 | uncertain significance | Cardiovascular phenotype | 2022-08-05 | criteria provided, single submitter | clinical testing | The p.R2133C variant (also known as c.6397C>T), located in coding exon 39 of the FLNC gene, results from a C to T substitution at nucleotide position 6397. The arginine at codon 2133 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a subject with hypertrophic cardiomyopathy (HCM) (Cui H et al. Mol Genet Genomic Med, 2018 11;6:1104-1113). 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. |