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

gnomAD frequency: 0.00001  dbSNP: rs397516348

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000159221	SCV000059943	uncertain significance	not provided	2020-11-02	criteria provided, single submitter	clinical testing	The p.Thr143Asn variant in TNNI3 has been reported by our laboratory in 3 individuals with early onset HCM, two of whom had an additional pathogenic variant in 1 or more genes (LMM data, Walsh 2017 PMID: 27532257, Bales 2016 PMID: 26936621). In one family, this variant was identified with another pathogenic variant associated to cardiomyopathy in an affected parent but not the second pathogenic one identified in the proband (LMM data). This variant was also identified in two individuals from HCM families that underwent genetic testing but who did not yet present with clinical symptoms (Valente 2013 PMID: 23690394). Additionally, the p.Thr143An variant been reported by other clinical laboratories in ClinVar (Variation ID: 43382) has been also been identified in 0.005% (6/113252) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Mouse studies have shown that phosphorylation at threonine 143 (position 144 in mice) plays an important role in the regulation of muscle contractility (Noland 1995 PMID:7592712, Vahebi 2005 PMID: 15774859, Wang 2006 PMID: 17010989, Mathur 2008 PMID: 17872964). Computational and conversation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr143Asp variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: PS3_Moderate.
GeneDx	RCV000159221	SCV000209167	uncertain significance	not provided	2020-01-16	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 17010989, 26526134, 23690394, 25228707, 30731207, 26936621, 21310275, 17872964, 15774859, 7592712)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628944	SCV000749852	uncertain significance	Hypertrophic cardiomyopathy	2024-03-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 143 of the TNNI3 protein (p.Thr143Asn). This variant is present in population databases (rs397516348, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of TNNI3-related conditions (PMID: 26936621, 27532257, 30731207, 34540771; Invitae). ClinVar contains an entry for this variant (Variation ID: 43382). 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 tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TNNI3 function (PMID: 15774859, 17010989, 17872964). 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 Diagnostics, LLC DBA Color Health	RCV001192353	SCV001360400	uncertain significance	Cardiomyopathy	2024-02-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 143 of the TNNI3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. Experimental studies have suggested that this variant may abolish the phosphorylation site and may therefore have a deleterious impact on the protein function (PMID: 15774859, 17010989, 17872964). However, clinical significance of these observations is unclear. This variant has been reported in individuals affected with or suspected to be affected with hypertrophic cardiomyopathy (PMID: 23690394, 26936621, 27532257, 30731207, 32481709). Three of these individuals also carried pathogenic variants in the MYBPC3 and TPM1 gene (PMID: 26936621). It has also been reported in one individual affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771). This variant has 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.
Klaassen Lab, Charite University Medicine Berlin	RCV002054586	SCV002495733	likely pathogenic	Left ventricular noncompaction cardiomyopathy		criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV000628944	SCV004819060	uncertain significance	Hypertrophic cardiomyopathy	2024-06-11	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). 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 individuals affected with or referred for testing for hypertrophic cardiomyopathy (PMID: 23690394, 26936621, 27532257, 30731207). Three of these individuals also carried pathogenic variants in the MYBPC3 and TPM1 gene (PMID: 26936621). It has also been reported in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771). This variant has 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.
Ambry Genetics	RCV004018790	SCV004968959	uncertain significance	Cardiovascular phenotype	2020-12-18	criteria provided, single submitter	clinical testing	The c.428C>A (p.T143N) alteration is located in exon 7 (coding exon 7) of the TNNI3 gene. This alteration results from a C to A substitution at nucleotide position 428, causing the threonine (T) at amino acid position 143 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV004018790	SCV006070346	uncertain significance	Cardiovascular phenotype	2025-04-09	criteria provided, single submitter	clinical testing	PM1, PM2, PS4_supp, PP2, BP4
Clinical Genetics, Academic Medical Center	RCV000159221	SCV001922074	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159221	SCV001951831	uncertain significance	not provided		no assertion criteria provided	clinical testing