Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000685726 | SCV000813218 | pathogenic | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-04-07 | criteria provided, single submitter | clinical testing | This variant disrupts a region of the FLNC protein in which other variant(s) (p.Trp2710*) have been determined to be pathogenic (PMID: 15929027, 22961544, 26472074, 26969713). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 566018). This frameshift has been observed in individual(s) with dilated cardiomyopathy (PMID: 27908349, 28416588). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the FLNC gene (p.Asp2703Thrfs*69). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the FLNC protein and extend the protein by 45 additional amino acid residues. |
| Gene |
RCV003226966 | SCV003923870 | likely pathogenic | not provided | 2023-09-25 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein elongation as the last 23 amino acids are replaced with 68 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27908349, 21135393, 31514951, 28416588, 31918855, 31924696, 34993393) |
| Ambry Genetics | RCV004026209 | SCV005017823 | uncertain significance | Cardiovascular phenotype | 2019-09-26 | criteria provided, single submitter | clinical testing | The c.8107delG variant, located in coding exon 48 of the FLNC gene, results from a deletion of one nucleotide at nucleotide position 8107, causing a translational frameshift with a predicted alternate stop codon (p.D2703Tfs*69). This variant was initially reported in a family with myofibrillar myopathy; however, the publication was retracted as it was determined the variant occurred on the FLNC pseudogene (Kono S et al. Neurology. 2010 Aug;75(6):547-54; van der Ven PF et al. Neurology. 2010 Dec;75(23):2137-8). This variant has been detected in two individuals with dilated cardiomyopathy (DCM) and arrhythmia from one family where pseudogene interference was reportedly excluded, and has also been detected in a DCM cohort; however, clinical details were limited (Ortiz-Genga MF et al. J. Am. Coll. Cardiol., 2016 Dec;68:2440-2451; Dal Ferro M et al. Heart, 2017 11;103:1704-1710). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of FLNC, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 45 amino acids. The exact functional impact of these inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| OMIM | RCV003237321 | SCV003935309 | pathogenic | Arrhythmogenic right ventricular dysplasia, familial, 15 | 2023-06-26 | no assertion criteria provided | literature only |