Submissions for variant NM_001276345.2(TNNT2):c.310C>T (p.Arg104Cys)

dbSNP: rs727503513

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152104	SCV000200768	likely pathogenic	Restrictive cardiomyopathy	2014-01-22	criteria provided, single submitter	clinical testing	The Arg94Cys variant in TNNT2 has not been previously reported in individuals wi th cardiomyopathy or in large population studies. It has been detected in 1 chil d with RCM tested by our laboratory and parental testing revealed de novo occur rence, which strongly supports a pathogenic role. Arginine (Arg) at position 94 is highly conserved in evolution and the change to cysteine (Cys) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, 2 other likely disease-causing variants at this pos ition (Arg94His and Arg94Leu) have been reported in multiple individuals with HC M (Varnava 1999, LMM unpublished data). In summary, the low frequency, computati onal prediction for this variant, and presence of other disease-causing variants at this position all suggest that the Arg94Cys variant is likely to be pathogen ic, but additional studies are needed to fully establish its clinical significan ce.
GeneDx	RCV000159282	SCV000209228	pathogenic	not provided	2017-08-21	criteria provided, single submitter	clinical testing	p.Arg94Cys (CGC>TGC): c.280 C>T in exon 9 of the TNNT2 gene (NM_001001430.1). The Arg94Cys mutation in the TNNT2 gene has been reported in association with HCM (D'Cruz L et al., 2000). D'Cruz et al. reported Arg94Cys as a de novo mutation in a female patient with HCM and it was not observed in 120 control individuals. Additionally, the Arg94Cys mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Other mutations at this codon (Arg94His, Arg94Leu) and in nearby residues (Arg92Gln, Arg92Leu, Arg92Trp, Glu96Lys) have been reported in association in association with cardiomyopathy, further supporting the functional importance of this region of the protein. In summary, Arg94Cys in the TNNT2 gene is interpreted as a disease-causing mutation. Hereditary hypertrophic cardiomyopathy (HCM) is primarily an autosomal dominant disease characterized by myocardial hypertrophy in the absence of other cardiac or systemic causes. HCM is most frequently caused by mutations in genes coding for sarcomeric proteins in the cardiac muscle leading to myocyte disarray, a hallmark feature of HCM. Less commonly, ventricular hypertrophy is a presenting feature of genetic systemic disorders, such as Danon disease, Fabry disease, or mitochondrial cardiomyopathy. HCM has a variable clinical presentation; including palpitations, chest pain, heart failure syncope, or sudden death, although some individuals may be asymptomatic (Marian A et al., 1995; Maron B, 2002). Mutations in the TNNT2 gene have been reported in 5-15% of patients with autosomal dominant familial hypertrophic cardiomyopathy, often characterized by minimal left ventricular hypertrophy (LVH) but a high incidence of sudden cardiac death (Moolman J et al., 1997; Cirino A et al., 2011). Mutations in TNNT2 have been reported less frequently in association with autosomal dominant familial dilated cardiomyopathy (Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae	RCV000533469	SCV000644768	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the TNNT2 protein (p.Arg94Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 10978365, 22112859, 23711808, 24111713; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 165549). 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%. This variant disrupts the p.Arg94 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10525521, 14654368, 14722098, 20031602, 20624503, 23283745). 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.
Ambry Genetics	RCV000619541	SCV000736122	pathogenic	Cardiovascular phenotype	2022-04-05	criteria provided, single submitter	clinical testing	The p.R94C pathogenic mutation (also known as c.280C>T), located in coding exon 8 of the TNNT2 gene, results from a C to T substitution at nucleotide position 280. The arginine at codon 94 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been detected as a confirmed de novo alteration in one individual with hypertrophic cardiomyopathy (HCM) (D'Cruz LG et al. J Med Genet. 2000;37:E18). This mutation has also been reported in several other unrelated HCM cases and in one restrictive cardiomyopathy (RCM) case (Otsuka H et al. Circ J. 2012;76:453-61; Liu W et al. Am J Cardiol. 2013;112:585-9; Berge KE et al. Clin Genet. 2014;86:355-60; Hayashi T et al. J. Hum. Genet., 2018 Sep;63:989-996). Two alterations affecting the same amino acid, p.R94H and p.R94L, have also been reported in association with HCM (Varnava A et al. Heart. 1999;82:621-4; Ripoll-Vera T et al. Rev Esp Cardiol (Engl Ed). 2016;69:149-58). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193334	SCV001362085	pathogenic	Primary familial hypertrophic cardiomyopathy	2019-09-06	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.280C>T (p.Arg94Cys) results in a non-conservative amino acid change located in the T1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.280C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy, one of whom was reportedly a proband with a de-novo occurrence of this variant (D'Cruz_2012, Otsuka_2012, Liu_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, although mutations spanning residues 92-110 of TNNT2 have been reported to impair tropomyosin-dependent functions of troponin T (Palm_2001) supporting a critical domain function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV003453110	SCV004181488	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453111	SCV004181489	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453109	SCV004181490	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159282	SCV000280518	likely 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. p.Arg94Cys (R94C; c.280C>T) in the TNNT2 gene This Arg94Cys variant has been reported in at least 2 unrelated cases of HCM—with no segregation or functional data available. Arg94Cys was first reported by D’Cruz et al. (2000), and was de novo in the HCM patient. Both parents tested negative for the variant and had normal EKGs and echocardiograms. Paternity was genetically confirmed. The paper showed the variant to be due to the C>T transition of a methylated cytosine in a CpG dinucleotide. Mogensen et al. (J Med Genet 2003 May;40(5):e59) apparently identified Arg94Cys in an HCM patient as part of a comparative study of two sequencing methods. However, the variant is not listed in the published paper itself, and the website link given for supplementary data is nonfunctional—so this could not be confirmed. (It is unclear if this is the same case.) Otsuka et al. (2011) found it in one Japanese proband. There is no published segregation data available. Another variant at this same codon Arg94Leu has been reported multiple times in association with HCM (and of note, it has been seen to cause sudden death in the absence of significant hypertrophy: Varvana et al 1999) and we would consider it likely disease causing. In ClinVar, LMM notes that another variant at this same codon, Arg94His, has been associated with HCM in at least 4 patients and that in one case it was de novo. 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 Val85Leu, Asp86Ala, Phe87Cys, Ile90Met, Arg92Trp, Arg92Gln, Arg92Leu, Lys97Asn and Ala104Val (HGMD; 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). In vitro functional data from Palm et al. (2001) suggests that a change at codon 94—specifically Arg94Leu—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Cysteine (capable of forming disulfide bridges). The Arginine at codon 94 is completely conserved across 39 vertebrate species examined. 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 over 60,000 published controls and individuals from publicly available population datsets. There is no variation at codon 94 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: D’Cruz et al. (2000) did not detect Arg94Cys in 120 multiethnic controls. Otsuka et al. (2011) did not observe it in 200 Japanese controls. Our patient’s ancestry is from Vietnam, and ancestry-matched individuals can be found in greater numbers in the ExAC database of ~60,000 exomes from disease-specific and population genetic studies (with efforts made to exclude individuals with severe pediatric diseases). ExAC contains individuals from multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian), including 4295 East Asians and 8256 South Asians. This variant is not present in ExAC.