Submissions for variant NM_000363.5(TNNI3):c.610C>T (p.Arg204Cys)

gnomAD frequency: 0.00001  dbSNP: rs727504243

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154213	SCV000203866	uncertain significance	not specified	2015-02-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg204Cys variant in TNNI3 has been identified by our laboratory in 1 child with features of RCM and HCM and 1 child with RCM and Vfib. The variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg204Cys variant may impact protein function (Cui 2013 [conference abstract]) . However, these types of assays may not accurately represent biological functio n. Additionally, a different amino acid alteration at this position (p.Arg204His ) is likely pathogenic and has also been identified in individuals with RCM and/ or HCM, supporting that a change at this position may not be tolerated. In summa ry, while there is some suspicion for a pathogenic role, the clinical significan ce of the p.Arg204Cys variant is uncertain.
GeneDx	RCV000159248	SCV000209194	pathogenic	not provided	2020-07-17	criteria provided, single submitter	clinical testing	Reported in association with HCM in the published literature (Van Driest et al., 2003; Gomes et al., 2004; Walsh et al., 2017); Published functional studies demonstrate increased calcium sensitivity compared to wild type (Nguyen et al., 2016); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12860912, 26199943, 27532257, 27895589, 15524171, 30165862)
Invitae	RCV000531443	SCV000623793	likely pathogenic	Hypertrophic cardiomyopathy	2023-06-16	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg204 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15698845, 18801787, 20569525, 29176140). 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: 27895589). 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. ClinVar contains an entry for this variant (Variation ID: 177631). This missense change has been observed in individuals with dilated cardiomyopathy, restrictive cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 33906374, 34036930). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the TNNI3 protein (p.Arg204Cys).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470778	SCV002767603	pathogenic	Cardiomyopathy	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, 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). (N) 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). (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 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). (P) 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. (P) 1002 - Moderate functional evidence supporting abnormal protein function. Analysis of animal model muscle fibres found this variant results in increased calcium sensitivity and reduced interactions with Troponins C and T (PMID: 27895589). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159248	SCV000280513	pathogenic	not provided		no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg204Cys (c.610 C>T) in the TNNI3 gene. This variant has been reported online in one case of HCM (http://cardiogenomics.med.harvard.edu). It has also been seen by another genetic testing laboratory, in two individuals with a clinical diagnosis of restrictive cardiomyopathy (verbal report). None of these cases have been reported in the literature (though reviews and compendiums do refer to this variant). Another variant at the same codon has been reported in association with both HCM and RCM (p.Arg204His, Kimura et al 1997, Koga et al 1996, Doolan et al 2005). In addition, multiple variants have been reported at nearby codons (p.Glu202Gly, p.Gly203Arg, p.Gly203Ser, p.Lys205Gln, see Willot et al 2010 review). The Arginine at codon 204 is completely conserved across species as are the neighboring amino acids. In silico analysis (PolyPhen2) predicts the variant to be probably damaging. The testing lab noted that the variant was absent in 100 Caucasian individuals and 100 African-American individuals.