ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.611G>A (p.Arg204His) (rs727504275)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
GeneDx RCV000159249 SCV000209195 pathogenic not provided 2018-03-13 criteria provided, single submitter clinical testing The R204H pathogenic variant in the TNNI3 gene has been reported previously in association withcardiomyopathy (Doolan et al. 2005, Gambarin et al., 2008; Yang et al. 2010), and has been observedin several unrelated individuals tested for cardiomyopathy at GeneDx. Doolan et al. (2005) observedR204H in three members of a family, two of whom were diagnosed with HCM. Yang et al. (2010)reported R204H as a de novo variant in an infant with ventricular septal defect and restrictivecardiomyopathy. Gambarin et al. identified this variant in a female with RCM who underwent cardiactransplantation at 23 years of age and had a family history of sudden cardiac death in her brother.Although R204H represents a conservative amino acid substitution of a positively charged residue foranother, it alters a highly conserved position in cardiac troponin I (Doolan et al. 2005). Functionalstudies demonstrated that R204H results in decreased interaction between cardiac troponin I andcardiac troponin C and T (Doolan et al., 2005). Furthermore, R204H was not observed inapproximately 6,100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations.In summary, R204H in the TNNI3 gene is interpreted as a pathogenic variant.
Invitae RCV000469008 SCV000551899 likely pathogenic Hypertrophic cardiomyopathy 2016-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 204 of the TNNI3 protein (p.Arg204His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (PMID: 15698845, 20569525) and restrictive cardiomyopathy (PMID: 23906401, 18801787). ClinVar contains an entry for this variant (Variation ID: 177679). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function that has been reported in several affected individuals. However further functional and/or genetic data will be needed to fully stablished pathogenicity for this variant. For these reasons, it has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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

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