Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000541184 | SCV000651032 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 150 of the FLNC protein (p.Asp150Gly). This variant is present in population databases (rs760711912, gnomAD 0.007%). This missense change has been observed in individual(s) with arrythmogenic cardiomyopathy and congenital myopathy (PMID: 31127727, 32112656). ClinVar contains an entry for this variant (Variation ID: 472068). 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. |
| Gene |
RCV002291664 | SCV002584465 | uncertain significance | not provided | 2022-04-14 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Reported in association with congenital myopathy and arrhythmogenic cardiomyopathy (Westra et al., 2019; Verdonschot et al., 2020); This variant is associated with the following publications: (PMID: 31127727, 32112656) |
| Ambry Genetics | RCV002330944 | SCV002637580 | uncertain significance | Cardiovascular phenotype | 2023-08-28 | criteria provided, single submitter | clinical testing | The p.D150G variant (also known as c.449A>G), located in coding exon 2 of the FLNC gene, results from an A to G substitution at nucleotide position 449. The aspartic acid at codon 150 is replaced by glycine, an amino acid with similar properties. In one cohort study, this variant has been detected in individuals reported to have hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy; however, clinical details were limited, reports may overlap, and this variant co-occurred with variants in other cardiomyopathy-related genes in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Hum Mutat, 2020 Jun;41:1091-1111). This variant has also been detected in an individual reported to have congenital myopathy (Westra D. J Neuromuscul Dis. 2019 ;6(2):241-258). 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. |