Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV005682304 | SCV006370017 | uncertain significance | Cardiovascular phenotype | 2025-08-14 | criteria provided, single submitter | clinical testing | The p.R409C variant (also known as c.1225C>T), located in coding exon 4 of the MYPN gene, results from a C to T substitution at nucleotide position 1225. The arginine at codon 409 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV001226289 | SCV001398599 | uncertain significance | Dilated cardiomyopathy 1KK | 2024-05-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 409 of the MYPN protein (p.Arg409Cys). This variant is present in population databases (rs757431496, gnomAD 0.002%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25448463). This variant is also known as 10:69908204 C>T. ClinVar contains an entry for this variant (Variation ID: 449328). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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. |
| Laboratory for Molecular Medicine, |
RCV000520571 | SCV000712297 | uncertain significance | not specified | 2016-06-16 | criteria provided, single submitter | clinical testing | The p.Arg409Cys variant in MYPN has been reported in 1 individual with DCM (Cham i 2014). This variant has been identified in 2/66730 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs757 431496). Computational prediction tools and conservation analysis suggest that t he p.Arg409Cys variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In summary, the clinical signific ance of the p.Arg409Cys variant is uncertain. |
| Gene |
RCV000766771 | SCV000617320 | uncertain significance | not provided | 2017-08-17 | criteria provided, single submitter | clinical testing | The R409C variant in the MYPN gene has been reported previously as a variant identified via a whole exome sequencing study of 26 French families with dilated cardiomyopathy (Chami et al., 2014); however, additional family history, segregation, and phenotypic information was not provided. The R409C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R409C 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 not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R409C as a variant of uncertain significance. |