Submissions for variant NM_001276345.2(TNNT2):c.360T>G (p.Phe120Leu)

gnomAD frequency: 0.00001  dbSNP: rs727504331

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159288	SCV000209234	likely pathogenic	not provided	2018-11-27	criteria provided, single submitter	clinical testing	The F110L variant that is likely pathogenic in the TNNT2 gene has previously been reported in association with HCM and was found to segregate with HCM in at least three affected relatives from one family (Torricelli et al., 2003; Girolami et al., 2006; Olivotto et al., 2008; Coppini et al., 2014). Of note, a different nucleotide change resulting in the same amino acid substitution (c.328 T>C, p.F110L) has also been reported, and some publications only describe the variant at the protein level and do not specify the nucleotide substitution. The F110L (c.330 T>G) is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although the F110L variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, a different likely pathogenic missense variants at the same residue (F110I) has also been reported in association with HCM (Watkins et al., 1995; Anan et al., 1998; Yanaga et al., 1999; Konno et al., 2005).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000211744	SCV000740432	pathogenic	Primary familial hypertrophic cardiomyopathy	2017-07-24	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000159288	SCV000927398	likely pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001089627	SCV001245104	likely pathogenic	Wolff-Parkinson-White pattern; Hypertrophic cardiomyopathy	2018-02-09	criteria provided, single submitter	research	TNNT2 Phe110Leu had been previously identified in multiple HCM probands (Walsh R, et al., 2017; Coppini R, et al., 2014; GeneDx, Pers. Comm.) and in one family it was found to segregate to two affected family members (Torricelli F, et al., 2003). We identified this variant in 1 HCM proband and an affected parent. The proband also harbours a second mutation MYBPC3 p.Gly531Arg. The TNNT2 Phe110Leu variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict that this variant is deleterious. In summary, the variant has been reported in numerous cases, it is very rare in the general population, in silico tools predict the variant to impact protein function and the variant has segregated with disease in one family, therefore we classify TNNT2 Phe110Leu as 'Likely Pathogenic'.
Genome-Nilou Lab	RCV003453158	SCV004181442	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453159	SCV004181443	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453157	SCV004181444	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531982	SCV004359942	likely pathogenic	Cardiomyopathy	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 110 in the tropomyosin binding domain 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 14636924, 23074333, 27532257, 29875424, 23074333, 27532257, 29875424, 35514357). It has been shown that this variant segregates with disease in 3 affected individuals in one family (PMID: 14636924, 16858239, 18533079). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and left ventricular systolic dysfunction who also carried a pathogenic variant in the MYBPC3 gene (PMID: 32228044). This variant has been identified in 2/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Phe110Ile, is considered to be disease-causing (ClinVar variation ID: 12412), suggesting that phenylalanine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV003764947	SCV004569383	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 110 of the TNNT2 protein (p.Phe110Leu). This variant is present in population databases (rs727504331, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 14636924, 25524337). ClinVar contains an entry for this variant (Variation ID: 177807). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 33025817). This variant disrupts the p.Phe110 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9714088, 16115869, 33025817). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824804	SCV000204106	likely pathogenic	Hypertrophic cardiomyopathy	2013-02-08	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory