Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000536487 | SCV000651126 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2199 of the FLNC protein (p.Gly2199Arg). This variant is present in population databases (rs368977589, gnomAD 0.006%). This missense change has been observed in individual(s) with myofibrillar myopathy (PMID: 25208129). ClinVar contains an entry for this variant (Variation ID: 472138). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 |
RCV001584316 | SCV001812185 | likely benign | not provided | 2020-12-04 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 25208129) |
| Ambry Genetics | RCV002377136 | SCV002667621 | uncertain significance | Cardiovascular phenotype | 2019-01-31 | criteria provided, single submitter | clinical testing | The p.G2199R variant (also known as c.6595G>A), located in coding exon 40 of the FLNC gene, results from a G to A substitution at nucleotide position 6595. The glycine at codon 2199 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in one individual from a myofibrillar myopathy cohort; however, clinical details were limited (Semmler AL et al. Orphanet J Rare Dis, 2014 Aug;9:121). This amino acid position is highly conserved in available vertebrate species. 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. |
| Victorian Clinical Genetics Services, |
RCV002470909 | SCV002768942 | uncertain significance | Hypertrophic cardiomyopathy 26 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524). In distal myopathy (MIM#614065), NMD-predicted variants cause a loss of function, however missense variants have been shown to result in a toxic gain of function (PMID: 32112656). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely benign and as a VUS, and observed in a single individual with myofibrillar myopathy (ClinVar, PMID: 25208129). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |