Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000522328 | SCV000619026 | uncertain significance | not provided | 2018-01-25 | criteria provided, single submitter | clinical testing | The R2067H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2067H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. |
| Foundation for Research in Genetics and Endocrinology, |
RCV000852301 | SCV000928321 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement | 2019-06-19 | criteria provided, single submitter | clinical testing | A heterozygous variant c.6200G>A (p.Arg2067His) in exon 37 has been observed in FLNC gene. The proband born of a non-consanguineous marriage, presented with clinical indications of myopathy, ataxia, muscle incoordination and decreased power in lower limbs. The patient was observed with the said variant in an autosomal dominant mode of inheritance. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.0008% and 0.005% in the ExAC. The in-silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. In summary, the said variant meets our criteria to be classified as variant of uncertain significance based on the mode of inheritance, in silico prediction and allele frequency in population databases. |
| Invitae | RCV000823001 | SCV000963835 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2022-07-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2067 of the FLNC protein (p.Arg2067His). This variant is present in population databases (rs776520014, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 450439). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |
| Revvity Omics, |
RCV000522328 | SCV003833151 | uncertain significance | not provided | 2023-04-03 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004023570 | SCV005017747 | uncertain significance | Cardiovascular phenotype | 2023-10-08 | criteria provided, single submitter | clinical testing | The p.R2067H variant (also known as c.6200G>A), located in coding exon 37 of the FLNC gene, results from a G to A substitution at nucleotide position 6200. The arginine at codon 2067 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |