ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.358T>A (p.Phe120Ile) (rs121964858)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709767 SCV000840077 pathogenic Left ventricular noncompaction 6 2017-11-01 criteria provided, single submitter clinical testing The c.328T>A (p.Phe110Ile) variant has not been observed in general population but reported with high prevalence and segregation pattern in multiple hypertrophic cardiomyopathy (HCM) patients (PMID: 7898523, 9714088). It is well conversed during evolution and predicted to be deleterious by multiple in silica prediction software. This variant has been showed to dramatically increase Ca2+ sensitivity of force development in cardiac muscle preparation (PMID: 10617660). It has been also observed in other clinical labs and reported as pathogenic. At the same amino acid position, Phe110Ile (c.330T>G), Phe110Val, Phe110L are reported as deleterious variants. Based on the above evidences, we interpret this variant as pathogenic.
OMIM RCV000013223 SCV000033470 pathogenic Familial hypertrophic cardiomyopathy 2 1998-08-04 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223682 SCV000280521 pathogenic not provided 2013-01-30 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 Phe110Ile (F110I; c.340T>A at the nucleotide level) The variant has been reported in at least 14 unrelated cases of HCM, and has segregated with disease in all affected family members tested (from 8 families). This includes strong segregation data from one Japanese family, and good segregation data from at least 3 others—plus extensive in vitro functional data and a Phe110Ile transgenic mouse model prone to arrhythmias. Cases: Watkins et al. (1995) first reported this variant in a proband with HCM, accompanied by weak segregation data: The variant was also present in the only other affected member of the family. Koga et al. (1996) detected it in 2 different Japanese families. The variant was “present in all affected family members” (a total of 5 people), but specific segregation data for each family is not provided. Anan et al. (1998) identified 6 different Japanese HCM families with the Phe110Ile variant. In 4 families, segregation analysis was possible. The variant segregated with disease in the following number of family members in each family: 3 (max separation: 2nd degree); 3 (max separation: 1st degree); 4 (max separation: 2nd degree); 3 (max separation: 2nd degree). Lin et al. (2000) reported Phe110Ile variants in a large Japanese HCM family, associated with significant biventricular hypertrophy and a high incidence of sudden death. Phe110Ile segregated with disease in all 6 affected individuals, 2 of whom were severely-affected homozygotes. The most distantly-related affected carriers of the variant were 3rd degree relatives (cousins). One family member died suddenly at age 18 while running and could not be genotyped. Konno et al. (2003, 2005) reported Phe110Ile in 2 Japanese individuals (it is not clear if they are related). Otsuka et al. (2011) found the variant in two unrelated Japanese probands, and in a third unrelated Japanese proband who also carried a TNNT2 Pro80Ser variant inherited from the other parent. Transgenic mice expressing Phe110Ile did not develop significant cardiac hypertrophy or fibrosis, but the variant impaired acute exercise tolerance; muscle fibers containing the variant had increased calcium sensitivity of force and an increased “energy cost” (ratio of ATPase/force) compared to wildtype (Hernandez 2005). Baudenbacher et al. (2008) showed the variant created arrhythmia (VT) susceptibility in transgenic mice. Other changes at codon 110 have also been associated with disease: Phe110Leu (we classify as likely disease causing) and Phe110Val (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 is available for the Phe110Ile variant specifically: Yanaga et al. (1999) showed the variant to potentiate the maximum level of ATPase activity in cardiac myofibrils. Nakaura et al. (1999) showed it to increase maximum contractile activity of skinned cardiac muscle fibers. Szczesna et al. (2000) showed it increased calcium sensitivity of force development in skinned cardiac muscle preparations, and troponin complexes containing the variant had impaired activation of myosin-ATPase. Takahashi-Yanaga et al. (2001) showed Phe110Ile to impair multiple calcium-regulating functions of troponin: It impaired the inhibitory function of troponin I, enhanced the neutralizing function of troponin C, and potentiated the maximum ATPase activity of myofibrils. Data from Palm et al. (2001) suggests that the Phe110Ile variant impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. Hinkle & Tobacman (2003) also showed Phe110Ile to significantly weaken binding of troponin to actin-tropomyosin. This is a conservative amino acid change from a nonpolar Phenylalanine to a nonpolar Isoleucine (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”. The Phe110Ile variant is listed in dbSNP as rs121964858 and labeled “probable-pathogenic”, as submitted by OMIM staff at Johns Hopkins. Controls: In total the variant has not been seen in ~5760 published controls and publicly available population datasets. Given the majority of reported cases are Japanese, it is important to note that the variant was not observed in a total of 360 Japanese controls. 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: Watkins et al. (1995) did not observe the variant in more than 100 control individuals, ethnicity not specified. Koga et al. (1996) did not detect the variant in more than 100 Japanese controls. Anan et al. (1998) did not detect it in 50 Japanese controls. Lin et al. (2000) did not observe it in 10 Japanese controls. Otsuka et al. (2011) did not observe it in 200 Japanese controls.

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