ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.406C>T (p.Arg136Ter) (rs1393946566)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578828 SCV000680788 uncertain significance not provided 2017-03-06 criteria provided, single submitter clinical testing The R136X variant has not been published as pathogenic or reported as benign, to our knowledge. The R136X variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, R136X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. However, heterozygous missense variants account for the majority of variants reported in the Human Gene Mutation Database in association with restrictive cardiomyopathy (Stenson et al., 2014). These missense variants cause cardiomyopathy by altering the calcium sensitivity of contraction. Of the few loss-of-function variants reported, only one suggests haploinsufficiency as a disease mechanism (Kostareva et al., 2007). Therefore, heterozygous loss of function is not a well-established disease mechanism for the TNNI3 gene. By contrast, knockout mice that were homozygous null for the cardiac isoform of troponin I were born healthy but died of acute heart failure on day of life 18 (Huang et al., 1999). The juvenile onset of heart failure is likely due to early compensation by a fetal form of troponin I, whose expression is downregulated with postnatal development, subsequently leading to complete troponin I deficiency in these mice (Huang et al., 1999). The homozygous presence of the R136X variant likely results in absence of functional protein. It is likely that the complete absence of this essential regulator of muscle contraction would cause disease.
Invitae RCV001295096 SCV001484007 uncertain significance Hypertrophic cardiomyopathy 2020-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg136*) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 488853). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNI3 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.