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

dbSNP: rs121964858

Total submissions: 8

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	Dilated cardiomyopathy 1D	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.
Color Diagnostics, LLC DBA Color Health	RCV001804727	SCV002053515	pathogenic	Cardiomyopathy	2021-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 110 in the tropomyosin binding domain of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown the mutant protein to exhibit increased Ca2+ sensitivity of force development and impaired ATPase activation in cardiac muscle preparation (PMID: 10617660). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 9482583, 9714088, 22112859, 23494605, 9714088) and has shown strong segregate with disease in six families, where the variant was associated with variable cardiac morphologies and a favorable prognosis (PMID: 9714088). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804727	SCV003934662	pathogenic	Cardiomyopathy	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: TNNT2 c.328T>A (p.Phe110Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes. c.328T>A has been reported in the literature in multiple individuals affected with HCM, including families with segregation data (eg. Anan_1998, Lin_2000, etc). These data indicate that the variant is very likely to be associated with disease. Skinned papillary muscle fibers from transgenic mice expressing F110I and F110I-reconstituted human cardiac muscle preparations demonstrated increased Ca2 sensitivity of force and ATPase activity and impaired ATPase activation (Hernandez_2005, Szczesna_2000). Two 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	RCV000709767	SCV004181445	pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450627	SCV004181446	pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013223	SCV004181447	pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000013223	SCV000033470	pathogenic	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.