Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223745 | SCV000280556 | uncertain significance | not specified | 2014-12-02 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TTN p.Pro24060ThrfsX9 (c.72177dupT) Given the presence of truncating variants in TTN in 3% of control individuals and the lack of segregation for some identified truncating variants, this result is not sufficient enough to be used for predictive genetic testing and re consider this variant a variant of uncertain significance, probably disease-causing. This variant is novel. This variant caused a shift in reading frame starting at codon Proline 24060, changing it to a Threonine and creating a premature stop codon at position 9 of the new reading frame. This variant is expected to result in either abnormal, truncated protein product of loss of protein from this allele through nonsense-mediated mRNA decay. With >300 exons and >34,000 amino acids, TTN has the largest coding sequence in the genome, and the majority of the general population will have at least 1 rare (defined as a mean allele frequency <0.5%) missense or truncating variant at this locus. Truncating TTN variants have been shown by Herman D et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) and approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls. Herman et al. report that they observed strong cosegregation (lod score, 9.3) of nonsense and frameshift variants with clinical status among 60 members of 16 families affected by DCM, indicating an odds of approximately 1 in 10^9 that the segregation of these TTN variants occurred by chance. TTN truncating mutations found in subjects with dilated cardiomyopathy (as opposed to those found in subjects without the disease) were nonrandomly distributed within titin: they were overrepresented in the A-band region. Our patient's variant is also located in the A-band region of titin. However, while truncating variants in TTN have been associated with disease, truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al. 2012). In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families—pointing to the difficulty in determining variant pathogenicity for a specific truncating variant. Norton et al., identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 24060 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 1/29/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/29/14). |