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

dbSNP: rs727504275

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2024-01-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies demonstrated that p.(R204H) results in decreased interaction between cardiac troponin I and cardiac troponin C and T (PMID: 15698845, 27895589); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18801787, 27895589, 20617149, 27930701, 27532257, 24322056, 31912959, 16199542, 15698845, 29176140, 20569525, 33906374, 31737537)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469008	SCV000551899	pathogenic	Hypertrophic cardiomyopathy	2024-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 204 of the TNNI3 protein (p.Arg204His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or restrictive cardiomyopathy (PMID: 15698845, 18801787, 20569525, 27532257, 29176140). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 177679). 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. Experimental studies have shown that this missense change affects TNNI3 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	RCV005054161	SCV001430824	pathogenic	Hypertrophic cardiomyopathy 7	2019-08-26	criteria provided, single submitter	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000159249	SCV002103281	pathogenic	not provided	2016-11-23	criteria provided, single submitter	clinical testing	PP3, PM2, PS2, PS3, PS4
Ambry Genetics	RCV002354362	SCV002661109	pathogenic	Cardiovascular phenotype	2022-01-13	criteria provided, single submitter	clinical testing	The p.R204H pathogenic mutation (also known as c.611G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 611. The arginine at codon 204 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated cases with hypertrophic cardiomyopathy and restrictive cardiomyopathy, including reported de novo occurrences and pediatric-onset disease, and has shown some segregation with disease in families (Doolan A et al. J Mol Cell Cardiol, 2005 Feb;38:387-93; Ingles J et al. J Med Genet, 2005 Oct;42:e59; Gambarin FI et al. Heart, 2008 Oct;94:1257; Parvatiyar MS et al. J Biomed Biotechnol, 2010 Jun;2010:350706; Yang SW et al. Cardiol Young, 2010 Oct;20:574-6; Ding WH et al. Chin Med J (Engl), 2017 Dec;130:2823-2828; Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 02;19:192-203; Maurizi N et al. JAMA Cardiol, 2018 06;3:520-525; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Parrott A et al. Am J Med Genet C Semin Med Genet, 2020 03;184:116-123). This variant has been reported to impact protein-protein interactions and calcium sensitivity in in vitro assays (Doolan A et al. J Mol Cell Cardiol, 2005 Feb;38:387-93; Nguyen S et al. Front Physiol, 2016 Nov;7:520). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV004551331	SCV004106928	likely pathogenic	TNNI3-related disorder	2023-07-26	criteria provided, single submitter	clinical testing	The TNNI3 c.611G>A variant is predicted to result in the amino acid substitution p.Arg204His. This variant was reported in the heterozygous state in patients with arrhythmogenic disorders (Additional data, Marschall et al. 2019. PubMed ID: 31737537; Supplemental Tables, Walsh et al. 2017. PubMed ID: 27532257; Parrott et al. 2020. PubMed ID: 31912959; Ware et al. 2021. PubMed ID: 33906374). Functional studies showed that this variant impacts the protein function of Troponin I (Doolan et al. 2005. PubMed ID: 15698845). Of note, another missense variant affecting the same amino acid (p.Arg204Cys) has also been reported to be causative for hypertrophic cardiomyopathy (Ware et al. 2021. PubMed ID: 33906374). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786409	SCV005399210	pathogenic	Cardiomyopathy	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants functionally proven to cause a loss of function effect by decreasing calcium sensitivity cause dilated cardiomyopathy (DCM). Missense variants functionally proven to cause a gain of function effect by increasing calcium sensitivity cause hypertrophic cardiomyopathy (HCM) (PMID: 21533915). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Only a single family has been reported with a recessive form of inheritance (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 8). (I) 0251 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD. (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative missense change at the same residue (p.Arg204Cys) has been reported as pathogenic, and observed in patients with restrictive cardiomyopathy (RCM) and HCM (ClinVar, PMID: 27895589). (SP) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and reported in multiple patients with HCM, RCM and infantile ventricular septal defects (ClinVar, PMID: 27895589, PMID: 31912959, PMID: 20569525). Some of these reports were de novo. (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Analysis of porcine muscle fibres showed this variant results in increased calcium sensitivity and reduced interactions with Troponins C and T (PMID: 27895589). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign