Description
The T1028I variant of uncertain significance in the MYBPC3 gene has been reported previously in three individuals with HCM, and was absent in 854 control alleles (Kapplinger et al., 2014). The T1028I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T1028I 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. In addition, this substitution occurs at a position that is conserved in mammals. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in the same residue (T1028S) has been reported in association with HCM in a patient who also harbored a splice site variant on the other MYBPC3 allele (Morita et al., 2008). Additionally, variants in nearby residues (R1022C, R1022S, R1033W, R1033Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
