ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.485G>C (p.Arg162Pro) (rs397516354)

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
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000629031 SCV000059953 likely pathogenic Hypertrophic cardiomyopathy 2020-08-04 criteria provided, single submitter clinical testing The p.Arg162Pro variant in TNNI3 has been reported in at least 5 individuals with HCM and segregated with disease in 3 affected relatives from 1 family (Richard 2005 PMID: 12707239, Doolan 2005 PMID: 15698845, Ingles 2005 PMID: 16199542, Keller 2009, Coppini 2014 PMID: 25524337, Alfares 2015 PMID: 25611685, Gomez 2017 PMID: 28356264, Walsh 2017 PMID 27532257, LMM data). It was absent from large population studies. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 43390). In vitro functional studies provide some evidence that this variant may impact protein function (Doolan 2005 PMID: 15698845). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additionally, two other variants involving this codon, p.Arg162Gln and p.Arg162Trp, have been classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg162Pro variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP1, PS3_Supporting, PM5_Supporting.
Invitae RCV000629031 SCV000749941 pathogenic Hypertrophic cardiomyopathy 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 162 of the TNNI3 protein (p.Arg162Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15698845, 27532257, 25524337, 28356264). ClinVar contains an entry for this variant (Variation ID: 43390). Experimental studies have shown that this missense change is associated with a significant reduction in interaction between troponin I and troponin C within the cardiac troponin complex (PMID: 15698845). This variant disrupts the p.Arg162 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9241277, 15698845, 21799269, 21896538, 22429680, 27532257, 10806205, 11735257, 15607392, 22876777, 15698845, 15992656, 16352453), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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.