Submissions for variant NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)

dbSNP: rs397516457

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036576	SCV000060231	likely pathogenic	Hypertrophic cardiomyopathy	2018-03-19	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000159284	SCV000209230	pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrated altered calcium regulation of muscle contraction (Lu et al., 2003; Harada et al., 2004); 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: 14654368, 10525521, 28073646, 22144547, 27532257, 11606294, 14722098, 18258667, 23074333, 25611685, 32659924, 30165862, 20513729)
Invitae	RCV000468546	SCV000541917	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 94 of the TNNT2 protein (p.Arg94Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10525521, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43629). 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. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 14654368, 14722098). 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: 10978365). 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	RCV000619398	SCV000740033	pathogenic	Cardiovascular phenotype	2018-01-29	criteria provided, single submitter	clinical testing	The p.R94L pathogenic mutation (also known as c.281G>T), located in coding exon 8 of the TNNT2 gene, results from a G to T substitution at nucleotide position 281. The arginine at codon 94 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in several hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with disease in one small family (Varnava A et al. Heart. 1999;82:621-4; Melacini P et al. Eur Heart J. 2010 Sep;31(17):2111-23; Pasquale F et al. Circ Cardiovasc Genet. 2012 Feb;5(1):10-7). Functional in vitro analyses involving skinned cardiac fibers have suggested that this alteration affects TNNT2 protein function (Lu QW et al. J Mol Cell Cardiol. 2003;35:1421-7). In addition, alterations involving the same amino acid, p.R94C (c.280C>T) and p.R94H (c.281G>A), have been described in patients with HCM including de novo occurrences (D'Cruz LG et al. J Med Genet. 2000;37:E18; Millat G et al. Eur J Med Genet. 2010;53:261-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258056	SCV001434887	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D	2019-12-31	criteria provided, single submitter	clinical testing	The c.281G>T variant results in an amino acid change from an arginine to a leucine at codon 94 of the TNNT2 protein (p.Arg94Leu). The variant has been reported in an individual with familial hypertrophic cardiomyopathy (HCM) and segregates in the family (PMID: 10525521). It has also been reported in multiple unrelated individuals affected with HCM (PMID: 27532257). Functional studies support an effect of this variant on calcium-dependent force generation (PMID: 14654368). Different missense variants at this location (p.Arg94Cys, p.Arg94His) have been reported in association with HCM (PMID: 22112859, 23711808, 2003160, 20624503). This variant is not present in population databases (gnomAD). Therefore, this variant in the TNNT2 gene is classified as likely pathogenic.
Genome-Nilou Lab	RCV003450687	SCV004181481	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450688	SCV004181482	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450686	SCV004181483	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000036576	SCV004821980	likely pathogenic	Hypertrophic cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 94 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies using rabbit skinned muscle fibers have shown that this variant causes an increase in calcium sensitivity (PMID: 14654368, 14722098). In-vitro functional characterization studies have shown that this variant causes instability in the tropomyosin overlap complex (PMID: 11606294). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 10525521, 20513729, 22144547, 27532257, 28073646, 32659924, 33495597). It has been shown that this variant segregates with disease in two affected individuals in one family (PMID: 28073646). This variant has also been reported in an individual affected with restrictive cardiomyopathy (PMID: 30165862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg94His and p.Arg94Cys, are considered to be disease-causing (ClinVar variation ID: 43628 and 165549), suggesting that arginine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159284	SCV000280519	likely pathogenic	not provided	2014-09-03	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. TNNT2 variant Arg94Leu (R94L; c.281G>T at the nucleotide level) The variant has been reported in at least 3 unrelated cases of HCM with moderate segregation data in one family and functional data available. Varnava et al. (1999, 2001) identified this variant in an HCM family with a history of four SCD under age 45. It segregated with the disease in 3 affected family members tested, which included two siblings and their cousin. In addition, a child of one of the siblings who had an abnormal ECG but normal echo at age 6 also had the variant. Melacini et al. (2010) detected the variant in an Italian HCM transplant patient. Pasquale et al. (2011) detected it in an HCM patient followed in the UK. Another change at this same codon, Arg94Cys, has been associated with HCM (we consider that variant to be of uncertain significance, probably 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 Val85Leu, Asp86Ala, Arg92Trp, Arg92Gln, Arg92Leu, Lys97Asn and Ala104Val (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 the Arg94Leu variant impairs binding of troponin T to tropomyosin and makes the protein less effective at promoting the binding of tropomyosin to actin. Lu et al. (2003) found it increased the calcium sensitivity of force generation, but had no effect on the protein’s affinity for tropomyosin. Harada & Potter (2004) showed the variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. 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”. Pasquale et al. (2011) report that the SIFT prediction for the variant is “not tolerated”. In total the variant has not been seen in ~6190 published controls and publicly available population datasets. 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: Varnava et al. (1999) did not find the variant in 100 normal controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Melacini et al. (2010) did not find it in 400 (Italian?) controls. Pasquale et al. (2011) did not find it in 200 Caucasian controls.