ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.877C>T (p.Arg293Cys) (rs367785431)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036625 SCV000060280 uncertain significance not specified 2017-08-09 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201898 SCV000256666 uncertain significance Familial hypertrophic cardiomyopathy 1 2014-10-08 criteria provided, single submitter research This TNNT2 Arg293Cys variant was first reported by Richard P et al., (2003) as a novel variant in one HCM proband. It has since been identified in other HCM patients (Miliou A., et al 2005; Mook O., et al 2013). Limited segregation analysis by Miliou A., et al (2005) identified 1 family member (son) of the index case to be carrying the Arg293Cys variant. This relative had no echo features of HCM but had ECG criteria for the 'sub clinical form of the disease'. We have identified this variant in 1 HCM proband who also carries a second variant of uncertain significance in MYBPC3 (Gly5Trp). This patient was diagnosed at 62 years and has a maximal wall thickness of 20mm. This variant is present (MAF=0.00001) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational analyses (Polyphen2, CADD, SIFT, Grantham) support a potentially deleterious role. More evidence and additional data is needed to confirm the role of this variant. Thus, we classify this variant as having "uncertain significance".
Invitae RCV000466963 SCV000541914 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 286 of the TNNT2 protein (p.Arg286Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs367785431, ExAC 0.02%). This variant has been reported in many individuals affected with HCM (PMID: 12707239, 15958377, 23785128, 25524337). ClinVar contains an entry for this variant (Variation ID: 43676). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000618018 SCV000739915 uncertain significance Cardiovascular phenotype 2015-12-22 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000768532 SCV000886851 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing

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