Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000725327 | SCV000336071 | uncertain significance | not provided | 2015-10-09 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000725327 | SCV000574396 | uncertain significance | not provided | 2017-04-03 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the FKRP gene. The R352C variant has not been published as pathogenic or been reported as benign to our knowledge. This 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). The R352C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. |
| Ambry Genetics | RCV002401986 | SCV002710869 | uncertain significance | Cardiovascular phenotype | 2020-10-26 | criteria provided, single submitter | clinical testing | The p.R352C variant (also known as c.1054C>T), located in coding exon 1 of the FKRP gene, results from a C to T substitution at nucleotide position 1054. The arginine at codon 352 is replaced by cysteine, an amino acid with highly dissimilar properties. 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. |
| Mayo Clinic Laboratories, |
RCV000725327 | SCV004225416 | uncertain significance | not provided | 2023-05-02 | criteria provided, single submitter | clinical testing | PP3, PM2, PM3 |
| Labcorp Genetics |
RCV003754872 | SCV004464374 | likely pathogenic | Walker-Warburg congenital muscular dystrophy | 2023-01-23 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg352 amino acid residue in FKRP. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt FKRP protein function. ClinVar contains an entry for this variant (Variation ID: 283765). This variant has not been reported in the literature in individuals affected with FKRP-related conditions. This variant is present in population databases (rs751676482, gnomAD 0.001%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 352 of the FKRP protein (p.Arg352Cys). |