Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255623 | SCV000321970 | uncertain significance | not provided | 2018-01-16 | criteria provided, single submitter | clinical testing | The K36T variant in the TNNI3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a different pathogenic variant at the same residue (K36Q) has been reported in one family with three individuals diagnosed at young ages with DCM (Carballo et al., 2009). In addition, functional studies showed the K36Q variant had a similar effect on calcium affinity compared to other troponin pathogenic variants associated with cardiomyopathy (Carballo et al., 2009). K36T results in a semi-conservative amino acid substitution of a positively charged Lysine with a neutral, polar Threonine at a residue that is conserved in mammalian species. Furthermore, K36T was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several splice site algorithms predict the K36T variant either damages or destroys the natural splice donor site in exon 3 of the TNNI3 gene, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the consequence of this variant cannot be precisely determined. Given the available evidence, we interpret K36T as a variant of uncertain significance. |