ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.54166C>T (p.Arg18056Ter) (rs768431507)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184378 SCV000237003 pathogenic not provided 2017-08-07 criteria provided, single submitter clinical testing The R16415X pathogenic variant in the TTN gene has been previously reported in association with DCM (Haas et al., 2015). R16415X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Although other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012), R16415X is 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). Furthermore, R16415X was not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, this variant is pathogenic.
Invitae RCV000531903 SCV000642440 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-02-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Arg18056*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein This variant is present in population databases (rs768431507, ExAC 0.01%). This variant has been observed in individuals affected with dilated cardiomyopathy (PMID: 25163546, 27813223). This variant is also known as c.27547C>T, p.Arg9183X. ClinVar contains an entry for this variant (Variation ID: 202509). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223808 SCV000280551 uncertain significance not specified 2014-03-26 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.Arg16415Ter (R16415X): c.49243 C>T in exon 230 of the TTN gene (NM_001256850.1) The variant has been not been previously reported in the literature or clinvar and has not been previously seen in out patient population at Stanford. Truncating TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and were found in 3% of controls. Herman et al. 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, the presence of truncating TTN variants in controls indicates that not all such variants can be presumed to be pathogenic. Norton et al. (2013, Ray Hershberger’s group) found that not all TTN truncating variants segregate with disease. Herman et al. reported that TTN truncating mutations found in subjects with dilated cardiomyopathy (versus 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. In total the variant has not been seen in ~6000 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset (as of 12/2/2014), which currently includes variant calls on ~4000 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Filipino. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes (as of 12/2/2014). Our recommendation based on our additional review is that all first degree family members continue to have regular clinical screening as outlined below. We also recommend that any affected family members be tested for this variant to help give us more information about whether this variant segregates with disease in the family.

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.