ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.863G>C (p.Arg288Pro)

dbSNP: rs397516484
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham 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 2020-05-18 criteria provided, single submitter clinical testing Reported in ClinVar with conflicting classifications (ClinVar Variant ID# 177635; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Functional studies demonstrated that R278P alters Troponin binding (Lassalle et al., 2010); This variant is associated with the following publications: (PMID: 15201162, 23283745, 24793961, 12860912, 12974739, 20031601, 15958377, 27532257, 9154300, 25611685, 20057144)
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584829 SCV000692506 likely pathogenic 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 Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2020-07-29 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 likely pathogenic Cardiomyopathy 2020-09-25 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258055 SCV001434886 likely pathogenic Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D 2019-08-20 criteria provided, single submitter clinical testing This TNNT2 variant results in the replacement of an arginine with a proline amino acid at codon 278. This variant is not present in the gnomAD population database. It has also been observed in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 12974739, 15958377, 23283745, 24793961). In vitro functional studies suggest this variant affects protein binding (PMID: 20057144). In addition, other variants at this same codon (e.g, p.Arg278His) have also been reported in individuals with HCM. This TNNT2 variant is considered likely pathogenic.

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