Submissions for variant NM_001276345.2(TNNT2):c.266T>A (p.Ile89Asn)

dbSNP: rs121964855

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211864	SCV000060219	pathogenic	Hypertrophic cardiomyopathy	2022-08-24	criteria provided, single submitter	clinical testing	The p.Ile79Asn variant in TNNT2 has been reported in >10 individuals with HCM and segregated with disease in >15 affected relatives from two families (Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523, Varnava 2001 PMID: 11560853, Menon 2008 PMID: 18651846, Murphy 2016 PMID: 26914223, Walsh 201 PMID:27532257, LMM data). This variant has also been identified in 0.001% (1/68028) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). In vitro functional studies and animal models suggest that the p.Ile79Asn variant may impact protein function (Yanaga 1999 PMID: 10085122, Miller 2001 PMID: 11060294, Knollmann 2001 PMID: 11113119) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Strong, PM2_Supporting, PS3_Moderate, PP3.
GeneDx	RCV000159272	SCV000209218	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Multiple functional studies suggest that p.(I79N) impacts myofilament calcium sensitivity (Yanaga et al., 1999; Szczesna et al., 2000; Knollman et al., 2001; Miller et al., 2001; Sommese et al., 2013; Wang et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23663841, 11060294, 10617660, 21683708, 24367593, 26914223, 18651846, 21310275, 27532257, 28166811, 7898523, 8205619, 11113119, 22144547, 28241245, 23396983, 28640247, 28615295, 24510615, 11060291, 29217433, 31006259, 33673806, 33025817, 10085122)
Invitae	RCV000684789	SCV000285647	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 79 of the TNNT2 protein (p.Ile79Asn). This variant is present in population databases (rs121964855, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8205619, 18651846, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12408). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 10085122, 10617660, 11060291, 11113119, 21683708, 23663841). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000243910	SCV000319765	pathogenic	Cardiovascular phenotype	2022-06-23	criteria provided, single submitter	clinical testing	The p.I79N pathogenic mutation (also known as c.236T>A), located in coding exon 7 of the TNNT2 gene, results from a T to A substitution at nucleotide position 236. The isoleucine at codon 79 is replaced by asparagine, an amino acid with dissimilar properties. This mutation has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy and/or sudden cardiac death, and has been shown to segregate with disease in families (Thierfelder L et al. Cell 1994;77(5):701-12; Watkins HN et al. Engl J Med. 1995;332(16):1058-64; Varnava AM et al. Circulation 2001;104(12):1380-4). In one family, this mutation was identified in members with variable presentations, including features of hypertrophic, restrictive, or dilated cardiomyopathy (Menon SC et al. Clin Genet. 2008;74(5):445-54). Multiple in vitro functional studies and mice models have demonstrated abnormal protein function with altered calcium sensitivity, impairment of the inhibitory action of troponin I, and enhanced contractility of cardiac muscle (Yanaga F et al. J Biol Chem. 1999;274(13):8806-12; Szczesna D et al. J Biol Chem. 2000;275(1):624-30; Miller T et al. J Biol Chem. 2001;276(6):3743-55; Knollmann BC. J Biol Chem. 2001;276(13):10039-48; Sommese RF et al. PLoS ONE. 2013;8(12):e83403). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Blueprint Genetics	RCV000159272	SCV000927479	pathogenic	not provided	2017-11-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171170	SCV001333859	pathogenic	Cardiomyopathy	2017-12-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159272	SCV001713933	pathogenic	not provided	2019-04-08	criteria provided, single submitter	clinical testing	PS3, PS4, PP1_Strong, PM2, PP3
Genome-Nilou Lab	RCV000013218	SCV004181535	pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013219	SCV004181536	pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013217	SCV004181537	pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000013217	SCV000033464	pathogenic	Hypertrophic cardiomyopathy 2	2008-11-01	no assertion criteria provided	literature only
OMIM	RCV000013218	SCV000033465	pathogenic	Dilated cardiomyopathy 1D	2008-11-01	no assertion criteria provided	literature only
OMIM	RCV000013219	SCV000033466	pathogenic	Cardiomyopathy, familial restrictive, 3	2008-11-01	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159272	SCV000280514	pathogenic	not provided	2014-07-23	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.Ile79Asn (c.236T>A) in the TNNT2 gene. This variant has been reported in at least one family with HCM and a high burden of sudden death, one family with a range of cardiomyopathy phenotypes, and in one case of sudden cardiac death. Strong segregation data has been reported in both cardiomyopathy kindreds. Thierfelder et al (1994) and Watkins et al (1995) reported a family with 9 affected family members who all had this variant; four of these individuals suffered a sudden cardiac death. One of the individuals who died suddenly and had the variant was a 16 year old male who had normal clinical findings. Varnava et al (2001) reported the variant in a male who died suddenly at 16 years of age and had evidence of HCM on autopsy. They did not provide detailed phenotypic information about that individual. Menon et al (2008) reported a family with RCM, HCM, and DCM; all nine affected family members carried the p.Ile79Asn variant. Disease-associated variants have been reported in neighboring codons (p.Phe77Leu and p.Gly83Lys), indicating the functional significance of this region in the TNNT2 gene. This is a non conservative amino acid change with a nonpolar Isoleucine being replaced with a polar Asparagine. Isoleucine is completely conserved at position 79 in the cardiac troponin T sequence across all vertebrates. Transgenic mice with this variant do not develop cardiac hypertrophy, even with chronic exercise, however they do show increased calcium sensitivity of the ATPase activity and force development in cardiac myofilaments (Miller et al 2001). Knollman et al (2001) further characterized transgenic mice, concluding that the increased myofilament calcium sensitivity increases baseline contractility but leads to cardiac dysfunction during inotropic stimulation. Rust et al (1999) studied the variant in single adult cardiomyocytes and observed impaired expression of the mutant protein and a disabling of cardiac contraction in the submaximal range of myoplasmic calcium concentrations. Lin et al (1996) studied the equivalent variant in rats and found 50% faster thin filament movement over a surface coated with heavy meromyosin. The variant has also been found to decrease the calcium sensitivity of force production and increase the unloaded shortening velocity (Sweeney et al 1998). Palm et al (2001) found that p.Ile79Asn does not affect tropomyosin binding while variants in resides 92-110 do. Some authors have suggested that this variant and other variants in TNNT2 confer a greater risk of sudden cardiac death with less or even no hypertrophy (Watkins et al 1995; Varnava et al 2001). Certainly the family reported by Thierfelder et al (1994) and then Watkins et al (1995) had multiple cases of sudden death, several with little or no hypertrophy. However, the family reported by Menon et al (2008) had no cases of sudden death or ventricular arrhythmias. In total the variant has not been seen in ~6890 published controls and individuals from publicly available population datasets. There is no variation at codon 79 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of January 30th, 2013). The variant is listed in dbSNP and 1000 genomes but ony in reference to the OMIM entry (rs121964855) (as of January 30th, 2013). The variant was not observed in the following published control samples: Thierfelder et al (1994) did not observe the variant in 100 presumably healthy controls whose race is unspecified. Varnava et al (2001) did not find the variant in 90 controls whose ethnicity is unknown. The testing lab did not detect the variant in 200 individuals of either Caucasian or African American descent.
Genomics England Pilot Project, Genomics England	RCV000013217	SCV001760003	likely pathogenic	Hypertrophic cardiomyopathy 2		no assertion criteria provided	clinical testing