ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.57769C>T (p.Arg19257Ter) (rs794729275)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184241 SCV000236863 likely pathogenic not provided 2014-04-02 criteria provided, single submitter clinical testing )p.Arg17616Stop (R17616X) CGA>TGA: c.52846 C>T in exon 245 of the TTN gene (NM_001256850.1). The R17616X mutation in the TTN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. R17616X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, R17616X 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, R17616X in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics RCV000248842 SCV000320204 likely pathogenic Cardiovascular phenotype 2015-09-22 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000184241 SCV000927721 likely pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223817 SCV000280554 uncertain significance not specified 2014-05-16 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. p.Arg17616Stop (c.52846 C>T) in the TTN gene (NM_001256850.1) Given that 3% of controls have a vairant like this, the location of the variant within the gene, and the absence in controls, we consider it a variant of uncertain significance, probably disease causing. We do not recommend using this variant to assess risk in healthy relatives. We do recommend tesitng the affected father and any other affected relatives specifically for this variant to help clarify its role in disease. The variant is novel. I could find no online or published references. This substitution creates a premature stop codon. 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 et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM). 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. However, Herman et al (2012) also observed truncating TTN variants in approximately 3% of control individuals. In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families. 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. Herman et al (2012) observed that TTN truncating variants found in subjects with DCM (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 located in the A-band region of titin. Thus, while the findings of Herman et al (2012) provide strong evidence that truncating TTN variants contribute to familial DCM, it is still challenging to determine the significance of anyone individual truncating variant. In total the variant has not been seen in ~6500 individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of June 11th, 2014). There is a missense variant at this codon in 1 of 5968 individuals in ESP (p.Arg17616Gln).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.