ClinVar

Description

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 Arg92Leu (R92L; 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 strong functional data available both in vitro and in a transgenic mouse model. Varnava et al. (2001) detected Arg92Leu in one case of HCM. Some papers appear to list this variant as “Arg102Leu”: Forissier et al. (1996) first reported “Arg102Leu” in a French family, where it segregated with disease in 4 family members (two affected sisters, who each had an affected child). Richard et al. (2003) found it in one HCM patient recruited in France Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Trp, which we categorize as very likely disease causing, and p.Arg92Gln, which we categorize 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). 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. 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. Haim et al. (2007) showed altered calcium handling in isolated myocytes from transgenic Arg94Leu mice. He et al. (2007) showed that transgenic mice bearing the Arg92Trp or Arg92Leu mutation had a greater “energy cost” for cardiac muscle contraction than wild-type mice. The magnitude of these changes was mutation-specific: Arg92Trp hearts showed more severe energetic abnormalities and greater contractile dysfunction than Arg92Leu hearts. Guinto et al. (2009) showed diastolic dysfunction in transgenic mice carrying the variant, and altered calcium kinetics in isolated transgenic myocytes. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. 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 ~5540 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 ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Forissier et al. (1996) did not find it in 50 controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Richard et al. (2003) did not find the variant in 100 (European?) controls.