Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000686698 | SCV000814227 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 309 of the FLNC protein (p.Glu309Lys). This variant is present in population databases (rs781212262, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of myofibrillar myopathy and/or sporadic inclusion body myositis and frontotemporal dementia (PMID: 25617006, 26555887, 34411373). ClinVar contains an entry for this variant (Variation ID: 566787). 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. |
| Fulgent Genetics, |
RCV000765931 | SCV000897351 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002369830 | SCV002684305 | uncertain significance | Cardiovascular phenotype | 2023-07-11 | criteria provided, single submitter | clinical testing | The p.E309K variant (also known as c.925G>A), located in coding exon 5 of the FLNC gene, results from a G to A substitution at nucleotide position 925. The glutamic acid at codon 309 is replaced by lysine, an amino acid with similar properties. This variant has been detected in frontotemporal dementia and inclusion body myositis cohorts; however, details were limited (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68; Weihl CC et al. Neuromuscul Disord, 2015 Apr;25:289-96). This variant has also been detected in a proband with skeletal myopathy and atrial arrhythmia and a sibling with only atrial arrhythmia (Conte G. J Cardiovasc Electrophysiol. 2021 Oct;32(10):2777-2780). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| CHEO Genetics Diagnostic Laboratory, |
RCV003486916 | SCV004240688 | uncertain significance | Cardiomyopathy | 2023-01-11 | criteria provided, single submitter | clinical testing |