ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.610C>T (p.Arg204Cys) (rs727504243)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159248 SCV000209194 pathogenic not provided 2017-08-21 criteria provided, single submitter clinical testing The R204C pathogenic variant in the TNNI3 gene has been reported previously in association with HCM (Van Driest et al., 2003; Gomes et al., 2004; Walsh et al., 2017). In addition, the R204C variant has been observed in other unrelated individuals tested for cardiomyopathy at GeneDx. Functional studies show that this variant results in increased calcium sensitivity compared to the wild type (Nguyen et al., 2016). This variant results in a non-conservative amino acid substitution at a position that is conserved across species. A missense variant in the same residue (R204H) has been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Furthermore, the R204C variant is not observed in large population cohorts (Lek et al., 2016).
Invitae RCV000531443 SCV000623793 likely pathogenic Hypertrophic cardiomyopathy 2017-03-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 204 of the TNNI3 protein (p.Arg204Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs727504243, ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 177631). Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Experimental studies have shown that this missense change has a deleterious effect on TNNI3 interactions  (PMID: 27895589). A different missense substitution at this codon (p.Arg204His) has been determined to be pathogenic (PMID: 5698845, 20569525, 23906401, 18801787). This suggests that the arginine residue is critical for TNNI3 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported in affected individuals and affects a residue important for protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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.
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.

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