Submissions for variant NM_000364.4(TNNT2):c.854G>C (p.Arg285Pro) (rs397516484)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000154217	SCV000203871	uncertain significance	not specified	2013-02-13	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000225728	SCV000209270	likely pathogenic	not provided	2018-09-07	criteria provided, single submitter	clinical testing	The R278P variant that is likely pathogenic was identified in the TNNT2 gene. This variant has previously been published in association with HCM (described once as R285P due to use of alternate transcript, NP_000355.2) (Erdmann et al., 2003; Van Driest et al., 2003; Miliou et al., 2005; Zou et al., 2013; Bos et al., 2014). Miliou et al. (2005) and Erdmann et al. (2003) observed segregation of R278P with disease in affected relatives from two unrelated families. This variant has also been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was observed to segregate with disease in at least one family. In addition, a different likely pathogenic missense variant affecting the same residue (R278C) has been reported multiple times in association with HCM (Watkins et al., 1995; Garcia-Castro et al., 2003; Torricelli et al., 2003; Van Driest et al., 2003; Theopistou et al., 2004; Ingles et al., 2005; Gimeno et al., 2009; Millat et al., 2011; Brito et al., 2012; Ripoll-Vera et al., 2016). The R278P variant is not observed in large population cohorts (Lek et al., 2016). The R278P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies by Lassalle et al. (2010) demonstrated that R278P alters Troponin binding. Researchers concluded that changes in this region of the protein affect normal protein function (Lassalle et al., 2010). Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, R278P in the TNNT2 gene is interpreted as a likely pathogenic variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute	RCV000584829	SCV000692506	likely pathogenic	Familial hypertrophic cardiomyopathy 1	2017-03-14	criteria provided, single submitter	research	The TNNT2(NM_000364.3: c.854G>C; p.Arg285Pro) variant is reported in literature as TNNT2 (NM_001001430.2:c.833G>C Arg278Pro) and has been reported in multiple cases of HCM and was absent from 200 controls collectively (Zou Y, et al., 2012; Millou A, et al., 2005; Van Driest SL, et al., 2003; Erdmann J, et al., 1998; Abchee A & Marian AJ, 1997). The variant has also been reported to segregate with disease (Abchee A & Marian AJ, 1997; Miliou A, et al., 2005). The variant is absent from both the 1000 genomes project (http://www.1000genomes.org/) and Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease. Interestingly, different rare variants at this position (Arg278Cys and Arg278His) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools PolyPhen-2 and MutationTaster predict this variant to be "probably damaging" and "disease-causing" respectively, however SIFT predicts this variant to be "tolerated", and no prediction is called by PolyPhen-HCM. A functional study on this variant indicated that the TNNT2 Arg278Pro variant alters protein binding, and that any changes within this region of the protein will affect protein function (Lassalle MW, 2010). In summary, multiple unrelated HCM probands reported with the variant, rarity in general populations and functional studies supportive of a damaging effect on function, we have classified the TNNT2 Arg285Pro variant as "Likely Pathogenic".
Invitae	RCV000690741	SCV000818442	pathogenic	Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3	2018-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with proline at codon 278 of the TNNT2 protein (p.Arg278Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 15958377, 23283745, 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 177635). Experimental studies have shown that this missense change reduces the protein to protein interaction of TNNT2 with TnI (PMID: 20057144). The observation of one or more missense substitutions at this codon (p.Arg278Leu and p.Arg278Pro) in affected individuals suggests that this may be a clinically significant residue (PMID: 23233322, 12974739, 15958377, 23283745, 24793961). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769737	SCV000901159	pathogenic	Cardiomyopathy	2017-10-17	criteria provided, single submitter	clinical testing