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

dbSNP: rs397516354

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000629031	SCV000059953	likely pathogenic	Hypertrophic cardiomyopathy	2022-08-10	criteria provided, single submitter	clinical testing	The p.Arg162Pro variant in TNNI3 has been reported in at least 7 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives from 2 families (Richard 2003 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, Asatryan 2019 PMID: 30975432, Chung 2021 PMID: 33407484, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 43390) and was absent from large population studies. 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, this variant meets criteria to be classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PS4_Moderate, PP1, PM2_Supporting, PS3_Supporting, PM5.
Invitae	RCV000629031	SCV000749941	pathogenic	Hypertrophic cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15698845, 25524337, 27532257, 28356264). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 162 of the TNNI3 protein (p.Arg162Pro). ClinVar contains an entry for this variant (Variation ID: 43390). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg162 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9241277, 10806205, 11735257, 15607392, 15698845, 15992656, 16352453, 21799269, 21896538, 22429680, 22876777, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 15698845). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.
3billion	RCV002250504	SCV002521570	pathogenic	Hypertrophic cardiomyopathy 7	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.64; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043390). Different missense changes at the same codon (p.Arg162Gln, p.Arg162Leu, p.Arg162Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043389, VCV000161396, VCV000626844). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003162313	SCV003869157	likely pathogenic	Cardiovascular phenotype	2023-01-12	criteria provided, single submitter	clinical testing	The p.R162P variant (also known as c.485G>C), located in coding exon 7 of the TNNI3 gene, results from a G to C substitution at nucleotide position 485. The arginine at codon 162 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in several unrelated individuals reported to have hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation, 2003 May;107:2227-32; Doolan A et al. J. Mol. Cell. Cardiol., 2005 Feb;38:387-93; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Gómez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Asatryan B et al. Am J Cardiol, 2019 06;123:2031-2038). In an in vitro study, this variant was reported to impact protein-protein interactions of the troponin complex (Doolan A et al. J. Mol. Cell. Cardiol., 2005 Feb;38:387-93). Other variants affecting this codon (p.R162Q, c.485G>A and p.R162W, c.484C>T) have also been reported in association with HCM (Mogensen J et al. J Am Coll Cardiol. 2004; 44(12):2315-25; Garcia-Pavia P et al. Eur. J. Heart Fail. 2011;13:1193-201). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.