Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000688028 | SCV000815624 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1710 of the FLNC protein (p.Glu1710Lys). This variant is present in population databases (rs200077114, gnomAD 0.007%). 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: 567840). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. |
| Fulgent Genetics, |
RCV000764685 | SCV000895817 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002334266 | SCV002642252 | uncertain significance | Cardiovascular phenotype | 2022-04-06 | criteria provided, single submitter | clinical testing | The p.E1710K variant (also known as c.5128G>A), located in coding exon 30 of the FLNC gene, results from a G to A substitution at nucleotide position 5128. The glutamic acid at codon 1710 is replaced by lysine, an amino acid with similar properties. This amino acid position is 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317339 | SCV004020842 | uncertain significance | not specified | 2023-06-23 | criteria provided, single submitter | clinical testing | Variant summary: FLNC c.5128G>A (p.Glu1710Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249506 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05), suggesting that the variant may be benign, however this should be interpreted with caution as the number of individuals with the variant is small. To our knowledge, no occurrence of c.5128G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |