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 variant Phe110Leu (F110L; T>C at the nucleotide level) This variant has been reported in at least 2 unrelated cases of HCM, with segregation data available from one family. Toricelli et al. (2003) first reported Phe110Leu in an HCM patient from Tuscany. The variant segregated with disease in a proband, her mother, and her maternal grandfather. Olivotto et al. (2008) appear to be referring to that same proband. Girolami et al. (2006) detected the variant in another Italian proband. Other changes at codon 110 have also been associated with disease: Phe110Ile (which we classify as very likely disease causing) and Phe110Val (which we classify as 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. This includes Ala104Val (HCM) and Arg113Trp (DCM) (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 110—specifically Phe110Ile—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. This is a conservative amino acid change from a nonpolar Phenylalanine to a nonpolar Leucine (with a smaller side-chain). The Phenylalanine at codon 110 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 ~5550 published controls and publicly available population datasets. There is no variation at codon 110 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: Toricelli et al. (2003) did not find Phe110Leu in 150 healthy controls from Tuscany. Girolami et al. (2006) did not find it in 100 Italian controls.