Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000560676 | SCV000651099 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1999 of the FLNC protein (p.Arg1999Gln). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or muscle weakness (PMID: 27574918, 30418145, 32528171; Invitae). ClinVar contains an entry for this variant (Variation ID: 472119). 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. |
| Baylor Genetics | RCV001332011 | SCV001524194 | uncertain significance | Myofibrillar myopathy 5 | 2019-02-22 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 27574918] |
| Fulgent Genetics, |
RCV002497177 | SCV002812718 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26 | 2021-09-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004024196 | SCV004871161 | uncertain significance | Cardiovascular phenotype | 2024-01-25 | criteria provided, single submitter | clinical testing | The c.5996G>A (p.R1999Q) alteration is located in exon 36 (coding exon 36) of the FLNC gene. This alteration results from a G to A substitution at nucleotide position 5996, causing the arginine (R) at amino acid position 1999 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/248984) total alleles studied. The highest observed frequency was 0.004% (4/112904) of European (non-Finnish) alleles. This alteration has been reported in an individual from a cohort of patients with hypertrophic cardiomyopathy (Jaafar, 2016). This alteration has also been reported in a cohort of patients with unexplained limb girdle weakness and/or elevated creatine kinase (Töpf, 2020). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |