Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000159304 | SCV000209250 | uncertain significance | not provided | 2013-11-25 | criteria provided, single submitter | clinical testing | p.Lys190Thr (AAG>ACG): c.569 A>C in exon 11 of the TNNT2 gene (NM_001001430.1). The Lys190Thr variant in the TNNT2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Lys190Thr variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. The Lys190 residue is class conserved across species. In silico analysis predicts Lys190Thr is probably damaging to the protein structure/function. Mutations in nearby residues (Ser179Phe, Arg205Trp) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. The Lys190Thr 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. With the clinical and molecular information available at this time, we cannot definitively determine if Lys190Thr is a disease-causing mutation or a rare benign variant. Hereditary dilated cardiomyopathy (DCM) is primarily an autosomal dominant disease characterized by left ventricular enlargement and systolic dysfunction in the absence of other cardiac, systemic or environmental causes (Hershberger R et al., 2009). Left ventricular noncompaction (LVNC) is a rare cardiomyopathy characterized by deep trabeculations with intertrabecular recesses in the ventricular wall (Callis T et al., 2010). LVNC and DCM can lead to progressive deterioration of cardiac function, arrhythmias, and sudden cardiac death, although some individuals may be asymptomatic. Hereditary DCM is most frequently caused by mutations in genes encoding for sarcomeric proteins in the cardiac muscle, or in the gene encoding the nuclear envelope protein lamin A/C (LMNA). Less commonly, DCM and LVNC can be caused by mutations in genes associated with metabolic or mitochondrial disorders (Callis T et al., 2010; Hershberger R et al., 2009). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). The variant is found in DCM-CRDM panel(s). |