ClinVar Miner

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

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000629031 SCV000749941 pathogenic Hypertrophic cardiomyopathy 2018-11-30 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000629031 SCV000059953 likely pathogenic Hypertrophic cardiomyopathy 2018-05-10 criteria provided, single submitter clinical testing The p.Arg162Pro variant in TNNI3 has been reported in at least 4 individuals wit h HCM, and segregated with disease in 3 individuals from 1 family (Richard 2005, Doolan 2005, Ingles 2005, Keller 2009, Coppini 2014, Alfares 2015, LMM data). I t was absent from large population studies. In vitro functional studies provide some evidence that this variant may impact protein function (Doolan 2005); howev er, these types of assays may not accurately represent biological function. Two other variants involving this codon, p.Arg162Gln and p.Arg162Trp, have been clas sified as likely pathogenic by this laboratory. Computational prediction tools a nd conservation analysis suggest that the p.Arg162Pro variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, although additional studies are required to fully establish its c linical significance, the p.Arg162Pro variant is likely pathogenic. ACMG/AMP Cri teria applied: PM2; PM5; PP1; PP3; PS4_Supporting.

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