Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001234393 | SCV001407037 | uncertain significance | Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant | 2022-09-13 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 377 of the FLNC protein (p.Lys377Asn). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 960797). |
| Molecular Genetics, |
RCV002221268 | SCV002498615 | uncertain significance | Myofibrillar myopathy 5 | 2021-09-03 | criteria provided, single submitter | clinical testing | This sequence change in FLNC is predicted to replace lysine with asparagine at codon 377 (p.(Lys377Asn)). The lysine residue is highly conserved (100 vertebrates, UCSC), and is located in the ROD1 Ig-like 2 domain (PMID: 32112656). There is a moderate physicochemical difference between lysine and asparagine. This variant is absent from gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature in any individuals with myopathy and has been classified as a variant of uncertain significance (LOVD, ClinVar ID: 960797). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3. |