Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000523034 | SCV000621531 | likely pathogenic | not provided | 2017-10-10 | criteria provided, single submitter | clinical testing | The c.95635_95638dupACTG variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). Additionally, c.95635_95638dupACTG causes a shift in reading frame starting at codon glycine 31880, changing it to an aspartic acid, and creating a premature stop codon at position 25 of the new reading frame, denoted p.Gly31880AspfsX25. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the TTN gene have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014). However, c.95635_95638dupACTG is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Other truncating variants in the M-band of titin, where this variant occurs, have been reported in association with an autosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents were reportedly healthy. Furthermore, other nonsense and frameshift TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). |