ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.508C>T (p.Arg170Trp) (rs727503504)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157530 SCV000205787 likely pathogenic Restrictive cardiomyopathy 2015-05-12 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000159231 SCV000209177 pathogenic not provided 2016-10-10 criteria provided, single submitter clinical testing This variant has not been published as pathogenic nor been reported as a benign to our knowledge, however it has been observed at GeneDx in the absence of any other pathogenic variants in multiple individuals with a diagnosis of RCM at less than 10 years of age. Additionally, this variant was found to be de novo in an individual referred for cardiomyopathy genetic testing at GeneDx. The R170W variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R170W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Lastly, a missense variant in the same residue (R170Q) has been reported in association with cardiomyopathy and observed de novo in a child with RCM (Kaski J et al., 2009; Mouton et al., 2015). In summary, this variant is pathogenic.
Invitae RCV000456293 SCV000551892 pathogenic Hypertrophic cardiomyopathy 2020-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 170 of the TNNI3 protein (p.Arg170Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with restrictive cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 179285). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg170Trp) is reported to be deleterious (PMID: 20031618 and ClinVar Variation ID: 165516). This indicates that the p.Arg170 residue is important for TNNI3 protein function. Furthermore, this variant occurs within a functional domain of the protein (p.Leu174-p.Ser210) that stabilizes the Ca2+ activated state of tropomyosin on actin filaments (PMID: 20035081, 21777381). Most of the TNNI3 variants associated with HCM are within this domain (PMID: 26440512). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics,University of Leuven RCV000456293 SCV000579526 pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score likely pathogenic
Blueprint Genetics RCV000157530 SCV000207276 likely pathogenic Restrictive cardiomyopathy 2014-07-15 no assertion criteria provided clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV001254049 SCV001429955 pathogenic Familial restrictive cardiomyopathy 1 2020-07-21 no assertion criteria provided clinical testing

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