Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000158213 | SCV000208148 | uncertain significance | not provided | 2017-10-19 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the MYBPC3 gene. The I1029N variant has not been published as pathogenic or been reported as benign to our knowledge. I1029N is not observed in large population cohorts (Lek et al., 2016). The I1029N 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. Moreover, 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. Although several missense variants in nearby residues (T1028I, T1028S, R1033W, R1033Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of each of these variants has not been definitively determined. Therefore, this variant lacks observation in a significant number of affected individuals and segregation data, which would further clarify its pathogenicity. |
| Invitae | RCV001042400 | SCV001206078 | uncertain significance | Hypertrophic cardiomyopathy | 2023-08-16 | criteria provided, single submitter | clinical testing | 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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 180998). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1029 of the MYBPC3 protein (p.Ile1029Asn). This variant is not present in population databases (gnomAD no frequency). |
| Ambry Genetics | RCV003380496 | SCV004089636 | uncertain significance | Cardiovascular phenotype | 2023-07-07 | criteria provided, single submitter | clinical testing | The p.I1029N variant (also known as c.3086T>A), located in coding exon 29 of the MYBPC3 gene, results from a T to A substitution at nucleotide position 3086. The isoleucine at codon 1029 is replaced by asparagine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |