Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001239831 | SCV001412732 | pathogenic | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg991*) in the FLNC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNC are known to be pathogenic (PMID: 27908349). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 27601210, 31317183, 31627847). ClinVar contains an entry for this variant (Variation ID: 267288). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002494806 | SCV002775862 | likely pathogenic | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26 | 2021-10-02 | criteria provided, single submitter | clinical testing | |
| Kardio |
RCV003991471 | SCV004809110 | likely pathogenic | Hypertrophic cardiomyopathy 26 | 2024-02-29 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV004017578 | SCV004848577 | pathogenic | Primary dilated cardiomyopathy | 2021-09-09 | criteria provided, single submitter | clinical testing | The p.Arg991X variant in FLNC has been reported in 4 individuals with dilated cardiomyopathy (DCM; Augusto 2019 PMID: 31317183). It has also been reported in 1 individual with arrhythmogenic cardiomyopathy and segregated with disease in 1 affected and 1 possibly affected relative from one family (Hall 2019 PMID: 31627847). Additionally, it has been identified in a boy with dysmorphic features and dilated cardiomyopathy (DCM), and in his brother with DCM, both of whom had an additional FLNC missense variant on the opposite allele, though multiple adults harboring only the p.Arg991X variant were asymptomatic (Reinstein 2016 PMID: 27601210). This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 267288) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 991, which is predicted to lead to a truncated or absent protein. Loss of function of the FLNC gene is an established disease mechanism in autosomal dominant DCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS4_Supporting. |
| Ambry Genetics | RCV004021050 | SCV005017687 | pathogenic | Cardiovascular phenotype | 2023-10-17 | criteria provided, single submitter | clinical testing | The p.R991* pathogenic mutation (also known as c.2971C>T), located in coding exon 20 of the FLNC gene, results from a C to T substitution at nucleotide position 2971. This changes the amino acid from an arginine to a stop codon within coding exon 20. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant co-occurred with a second FLNC alteration in trans in siblings reported to have dilated cardiomyopathy (DCM) in childhood, and extracardiac features (Reinstein E et al. Eur J Hum Genet, 2016 Dec;24:1792-1796). This variant has also been detected in additional individuals with features of arrhythmogenic cardiomyopathy, DCM, and myocarditis-like phenotypes (Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 Mar;21:326-336; Hall CL et al. Int J Cardiol, 2020 May;307:101-108; Peretto G et al. JACC Basic Transl Sci, 2023 Jul;8:755-765). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is expected to be causative of FLNC-related dilated cardiomyopathy; however, its clinical significance for FLNC-related hypertrophic/restrictive cardiomyopathy and/or skeletal myopathy is unclear. |