Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV001195430 | SCV001365785 | likely pathogenic | Primary dilated cardiomyopathy | 2019-11-13 | criteria provided, single submitter | clinical testing | The p.Arg25380AsnfsX7 variant in TTN has not been previously reported in individuals with dilated cardiomyopathy and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 25380 and leads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Arg25380AsnfsX7 variant is located in A-band in a highly expressed exon. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy. ACMG/AMP Criteria applied: PVS1, PM2. |