ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.428C>A (p.Thr143Asn) (rs397516348)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036291 SCV000059943 uncertain significance not specified 2017-08-30 criteria provided, single submitter clinical testing The p.Thr143Asn variant in TNNI3 has been reported in 1 individual with HCM and 3 individuals with early onset HCM, 2 of whom carried an additional pathogenic v ariant in another gene(Valente 2013; LMM data). It also segregated with disease in 2 affected relatives from 2 families. This variant has been identified in 6/1 11692 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs397516348) and has been reported in ClinVar (V ariation ID: 43382). Mouse studies have shown that phosphorylation at threonine 143 (position 144 in mice) plays an important role in the regulation of muscle c ontractility (Noland 1995, Vahebi 2005, Wang 2006, Mathur 2008). A change from t hreonine (Thr) to asparagine (Asn) abolishes this phosphorylation site and may t herefore have functional consequences. The variant was also predicted to be path ogenic using a computational tool clinically validated by our laboratory. This t ool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2 011). However, threonine (Thr) at position 143 is not conserved in evolution, an d asparagine (Asn) is present in multiple species (frog and 9 fishes). In summar y, the clinical significance of the p.Thr143Asp variant is uncertain due to conf licting data.
GeneDx RCV000159221 SCV000209167 likely pathogenic not provided 2013-02-15 criteria provided, single submitter clinical testing The T143N variant in the TNNI3 gene has not been reported previously as a disease causing mutation or as a benign polymorphism, to our knowledge. T143N represents a conservative amino acid substitution of one neutral, polar amino acid with another at a position that is conserved in mammals. Nevertheless, T143N is located in a region of the gene where several disease-causing mutations have been reported (R141Q, L144Q, R145Q, R145G), supporting the functional importance of this region of the protein.Gomes et al reported that T143 is a cardiac specific residue located in the inhibitory region of TNNI3 and that phosphorylation of T143 reduced the affinity of the main inhibitory region of cardiac troponin I for cardiac troponin C by nearly 14-fold. However, it is unknown if replacement of T143 with Asparagine has an effect on the phosphorylation status of cardiac troponin I or its interactions with other proteins. In addition, the T143N variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While T143N in the TNNI3 gene is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant. The variant is found in HCM panel(s).
Invitae RCV000628944 SCV000749852 uncertain significance Hypertrophic cardiomyopathy 2019-04-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 143 of the TNNI3 protein (p.Thr143Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs397516348, ExAC 0.006%). This variant has been reported in an individual affected with cardiomyopathy and in individuals referred for testing for hypertrophic cardiomyopathy (PMID: 27532257, 23690394). In addition, this variant has been reported in a parent and child with hypertrophic cardiomyopath. In this family, the parent carried a second missense variant in the TPM1 gene, and the child carried both a pathogenic variant in MYBPC3 and the variant in TPM1 (PMID: 26936621). ClinVar contains an entry for this variant (Variation ID: 43382). Experimental studies using an animal model have suggested that the threonine at position 143, corresponding to threonine at position 144 in mice, may be involved in phosphorylation and myofilament response to calcium regulation (PMID: 17010989, 17872964, 15774859). However, the clinical significance of these findings is unclear. An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001192353 SCV001360400 uncertain significance Cardiomyopathy 2020-11-24 criteria provided, single submitter clinical testing This missense variant replaces threonine with asparagine at codon 143 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Computational splicing tools suggest that this variant may not impact RNA splicing. Experimental studies have suggested that this variant may abolish the phosphorylation site and may therefore have deleterious impact on the protein function (PMID: 15774859, 17010989, 17872964). However, clinical significance of these observations is unclear. This variant has been reported in 8 individuals affected with or referred for testing for hypertrophic cardiomyopathy (PMID: 23690394, 26936621, 27532257). Three of these individuals also carried pathogenic variants in the MYBPC3 and TPM1 gene (PMID: 26936621). This variant has also been identified in 9/248930 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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