Submissions for variant NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)

gnomAD frequency: 0.00001  dbSNP: rs121964856

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211865	SCV000060229	pathogenic	Hypertrophic cardiomyopathy	2018-07-10	criteria provided, single submitter	clinical testing	The p.Arg92Gln variant in TNNT2 has been reported in >15 individuals with HCM, i ncluding one de novo occurrence, and segregated with disease in >15 affected rel atives (Thierfelder 1994, Watkins 1995, Morita 2008, Olivotto 2008, Strijack 200 8, Ripoll-Vera 2016, Walsh, 2017, LMM data). In addition, this was absent from l arge population studies. In vitro functional studies have shown that the Arg92Gl n variant impacts protein function (Marian 1997, Yanaga 1999, Robinson 2002, Liu 2012) and transgenic mice carrying this variant develop HCM (Chandar 2001, Ferr antini 2017). In summary, this variant meets criteria to be classified as pathog enic for HCM in an autosomal dominant manner based on case observations, segrega tion studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PS3, PS4, PP1_Strong, PM2.
GeneDx	RCV000159281	SCV000209227	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant impairs tropomyosin binding, calcium signaling, and the myofibrillar assembly (Yanaga et al., 1999; Javadpour et al., 2003; Liu et al., 2012; Robinson et al., 2018; Cai et al., 2020); 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: 30847666, 26507537, 27036851, 29760186, 29725858, 33336002, 31308319, 28735292, 21131475, 12479243, 11158969, 17932326, 12186860, 10085122, 10617660, 10449439, 12952925, 19087273, 24691700, 22675533, 8205619, 18403758, 9788962, 21310275, 27532257, 30022097, 31006259, 31759053, 33673806, 30975432, 26582918, 33025817, 11857753)
Invitae	RCV000627784	SCV000285648	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 92 of the TNNT2 protein (p.Arg92Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, left ventricular non-compaction, atypical pattern of myocardial scarring and/or inducible malignant ventricular tachyarrhythmia (PMID: 7898523, 8205619, 8951566, 18403758, 19087273, 19487599, 23233322, 24691700, 25524337). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12409). 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: 9788962, 10085122, 10449439, 11158969, 12186860). This variant disrupts the p.Arg92 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9060892, 16326803, 22144547). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000013220	SCV000299242	likely pathogenic	Hypertrophic cardiomyopathy 2	2016-03-08	criteria provided, single submitter	clinical testing	This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with HCM. Studies have shown that the variant impacts protein function (PMID:8205619).
Ambry Genetics	RCV000621709	SCV000735554	pathogenic	Cardiovascular phenotype	2022-03-07	criteria provided, single submitter	clinical testing	The p.R92Q pathogenic mutation (also known as c.275G>A), located in coding exon 8 of the TNNT2 gene, results from a G to A substitution at nucleotide position 275. The arginine at codon 92 is replaced by glutamine, an amino acid with highly similar properties. This alteration (also described as p.R102Q, c.305G>A) has been reported in association with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction (LVNC) and has shown strong segregation with disease across several families (Thierfelder L, Cell 1994 Jun; 77(5):701-12; Watkins H, N. Engl. J. Med. 1995 Apr; 332(16):1058-64; Torricelli F, Am. J. Cardiol. 2003 Dec; 92(11):1358-62; Strijack B, J Cardiovasc Magn Reson 2008; 10():58; Lopes LR, Heart 2015 Feb; 101(4):294-301; Tian T, Heart Vessels 2015 Mar; 30(2):258-64; Ripoll-Vera T, Rev Esp Cardiol (EnglEd) 2016 Feb; 69(2):149-58). One study also demonstrated this alteration as a de novo mutation in a subject with HCM (Morita H, N. Engl. J. Med. 2008 May; 358(18):1899-908). Several studies have also shown that this alteration has an impact on protein function (Yanaga F, J. Biol. Chem. 1999 Mar; 274(13):8806-12; Palm T, Biophys. J. 2001 Nov; 81(5):2827-37; Robinson P, Circ. Res. 2007 Dec; 101(12):1266-73; Liu B, PLoS ONE 2012; 7(6):e38259). In addition, transgenic mouse models have shown this alteration causes hypercontractility and diastolic dysfunction (Tardiff JC, J. Clin. Invest. 1999 Aug; 104(4):469-81; Oberst L, J. Clin. Invest. 1998 Oct; 102(8):1498-505; Chandra M, Am. J. Physiol. Heart Circ. Physiol. 2001 Feb; 280(2):H705-13). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV003450625	SCV004181491	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450626	SCV004181492	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013220	SCV004181493	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000013220	SCV000033467	pathogenic	Hypertrophic cardiomyopathy 2	1994-06-03	no assertion criteria provided	literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159281	SCV000280516	pathogenic	not provided	2012-01-16	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. Based on the strong case data, strong segregation data, and mouse models, we consider it very likely disease causing. The variant has been seen in at least 8 unrelated cases of HCM (not including the patient) with good segregation data in one family and extensive functional data available—including in transgenic mouse models. In our own center we have seen this variant in at least three unrelated individuals with familial cardiomyopathy. Thierfelder et al. (1994) identified Arg92Gln in one HCM family; it segregated with disease in all 6 affected members (degree of relationship not reported; LOD score 4.1). Watkins et al. (1995) identified Arg92Gln in 3 unrelated HCM families. (LOD score 8.3.) Torricelli et al. (2003) identified it in an HCM case from Tuscany. Morita et al. (2008) found it had occurred de novo in a patient with HCM. Paternity was confirmed, and the parents were clinically unaffected. Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Leu and p.Arg92Trp (we categorize both as very likely disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Glu83Lys, Val85Leu, Asp86Ala, Arg94Leu, Arg94Cys, and Lys97Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). Oberst et al. (1998) showed transgenic mice carrying Arg92Gln to have increased cardiac myocyte disarray, increased interstitial collagen synthesis, and diastolic dysfunction. Tardiff et al. (1999) also showed the transgenic mouse hearts to have increased interstitial fibrosis, hypercontractility, and diastolic dysfunction. In vitro functional data from Palm et al. (2001) suggests that a change at codon 92—whether Arg92Trp, Arg92Gln or Arg92Leu—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. Takahashi-Yanaga et al. (2001) showed the variant to impair the inhibitory effect of Troponin I on the sarcomere. Hinkle & Tobacman (2003) showed the variant to impair folding of the troponin T tail domain. Javadpour et al. (2003) found significant changes in cardiac energetics in transgenic mice carrying the variant. [[Note: Other papers to address the altered properties of myocytes containing this variant include Marian et al. 1997, Morimoto et al. 1998, Sweeney et al. 1998, Rust et al.1999, Yanaga et al. 1999, Szczesna et al. 2000, Chandra et al. 2001, Montgomery et al. 2001, Robinson et al. 2002, Solaro et al. 2002, Maass et al. 2004, and others. These are not reviewed here.]] Jimenez & Tardiff (2011) found Arg92Gln transgenic mice had an increased incidence of heart block and a greater frequency of premature ventricular contractions after isoproterenol injections. They also had abnormal autonomic regulation of heart rate. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Glutamine. The Arginine at codon 92 is highly conserved across 39 vertebrate species examined (it is a Lysine in medaka) and surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” In total the variant has not been seen in ~7030 published controls and publicly available population datsets. There is no variation at codon 92 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian African American individuals (as of July 2nd, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of July 2nd, 2014). The variant was not observed in published controls: Thierfelder et al. (1994) did not find Arg92Gln in 100 controls. Watkins et al. (1995) did not observe it in more than 100 control individuals, ethnicity not specified. Torricelli et al. (2003) did not find it in 150 healthy controls from Tuscany. Morita et al. (2008) did not find it in 180 ethnicity-matched controls.
Clinical Genetics, Academic Medical Center	RCV000159281	SCV001917971	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159281	SCV001953929	pathogenic	not provided		no assertion criteria provided	clinical testing