ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.611G>A (p.Arg204His) (rs727504275)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000469008 SCV000203935 likely pathogenic Hypertrophic cardiomyopathy 2015-05-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000159249 SCV000209195 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The R204H pathogenic variant in the TNNI3 gene has been reported previously in association withcardiomyopathy (Doolan et al. 2005, Gambarin et al., 2008; Yang et al. 2010), and has been observedin several unrelated individuals tested for cardiomyopathy at GeneDx. Doolan et al. (2005) observedR204H in three members of a family, two of whom were diagnosed with HCM. Yang et al. (2010)reported R204H as a de novo variant in an infant with ventricular septal defect and restrictivecardiomyopathy. Gambarin et al. identified this variant in a female with RCM who underwent cardiactransplantation at 23 years of age and had a family history of sudden cardiac death in her brother.Although R204H represents a conservative amino acid substitution of a positively charged residue foranother, it alters a highly conserved position in cardiac troponin I (Doolan et al. 2005). Functionalstudies demonstrated that R204H results in decreased interaction between cardiac troponin I andcardiac troponin C and T (Doolan et al., 2005). Furthermore, R204H was not observed inapproximately 6,100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations.In summary, R204H in the TNNI3 gene is interpreted as a pathogenic variant.
Invitae RCV000469008 SCV000551899 pathogenic Hypertrophic cardiomyopathy 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 204 of the TNNI3 protein (p.Arg204His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with restrictive cardiomyopathy (PMID: 29176140) and has been reported in several individuals affected with this disease or hypertrophic cardiomyopathy (PMID: 20569525, 18801787, 15698845, 27532257). ClinVar contains an entry for this variant (Variation ID: 177679). This variant has been reported to affect TNNI3 protein function (PMID: 27895589). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics,University of Leuven RCV000469008 SCV000579527 likely pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score likely pathogenic
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254739 SCV001430824 pathogenic Restrictive cardiomyopathy; Hypertrophic cardiomyopathy 2019-08-26 no assertion criteria provided research This variant has been identified in 1 HCM proband as part of our research program. Family screening identified two additional affected individuals, one family member was diagnosed with HCM and the other with RCM. The variant segregated to both affected family members (2 meiosis). For further information please feel free to contact us.

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.