Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000155924 | SCV000205635 | likely pathogenic | Primary dilated cardiomyopathy | 2014-05-22 | criteria provided, single submitter | clinical testing | The Phe24725fs variant in TTN has been identified in our laboratory in 1 Caucasi an individual with idiopathic cardiomyopathy and a family history of cardiomyopa thy and complex CHD. Data from large population studies is insufficient to asses s the frequency of this variant. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 24725 and leads to a premature termination codon 3 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Frameshift and oth er truncating variants in TTN are strongly associated with DCM and the majority occur in exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), where this variant is located. In summary, although additional studies ar e required to fully establish its clinical significance, the Phe24725fs variant is likely pathogenic. |
| Gene |
RCV000184340 | SCV000236965 | pathogenic | not provided | 2014-02-14 | criteria provided, single submitter | clinical testing | c.76955_76956delTT: p.Phe25652CysfsX3 (F25652CfsX3) in exon 276 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces is: ACTT{delTT}GTTC. Although the c.76955_76956delTT mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Phe25652, changing it to a Cysteine, and creating a premature stop codon at position three of the new reading frame, denoted p.Phe25652CysfsX3. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.76955_76956delTT is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.76955_76956delTT in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s). |