Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003011774 | SCV003305933 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2022-08-16 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 C15"). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2521 of the FLNC protein (p.Gly2521Arg). This variant also falls at the last nucleotide of exon 45, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV003274137 | SCV004004615 | uncertain significance | Cardiovascular phenotype | 2023-05-08 | criteria provided, single submitter | clinical testing | The c.7561G>C variant (also known as p.G2521R), located in coding exon 45 of the FLNC gene, results from a G to C substitution at nucleotide position 7561. The amino acid change results in glycine to arginine at codon 2521, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 45, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. In addition, as a missense substitution this 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. |