Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000540744 | SCV000650969 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2022-07-12 | 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 1002 of the FLNC protein (p.Arg1002Gln). This variant is present in population databases (rs202039743, gnomAD 0.006%). 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: 472025). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| Gene |
RCV000658214 | SCV000779985 | uncertain significance | not provided | 2018-12-19 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the FLNC gene. The R1002Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1002Q variant is observed in 7/126432 (0.01%) alleles from individuals of European background (Lek et al., 2016). The R1002Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Ambry Genetics | RCV003159895 | SCV003859302 | uncertain significance | Cardiovascular phenotype | 2022-11-21 | criteria provided, single submitter | clinical testing | The p.R1002Q variant (also known as c.3005G>A), located in coding exon 20 of the FLNC gene, results from a G to A substitution at nucleotide position 3005. The arginine at codon 1002 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |