ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.887G>A (p.Arg296His) (rs141121678)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036626 SCV000060281 uncertain significance not specified 2018-07-16 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg286His var iant in TNNT2 has been reported in >13 individuals with HCM and segregated with disease in at least 1 affected relative (Van Driest 2003, Van Driest 2004, Ande rsen 2009, Zhao 2016, Ripoll-Vera 2016, Viswanathan 2017). This variant has been identified in 0.09% (16/18472) of East Asian chromosomes by the Genome Aggregat ion Database (gnomAD, and is reported in Clin Var (Variation ID: 43677). Computational prediction tools and conservation analy sis suggest that the p.Arg286His variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Arg286His variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS4, P P3, BS1.
GeneDx RCV000223838 SCV000209271 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing The R286H variant has been reported in multiple individuals with a diagnosis of HCM (referred to in one paper as R296H due to alternative nomenclature) (Van Driest et al., 2003; Van Driest et al., 2004; Andersen et al., 2009; Yang et al., 2011; Chiou et al., 2014; Zhao et al., 2016; Walsh et al., 2017; Mademont-Soler et al., 2017). The R286H variant was initially reported in two unrelated individuals with HCM (Van Driest et al., 2003). A subsequent study by the same group determined that one of these individuals also harbored a variant in the MYBPC3 gene, which was consistent with the severe HCM phenotype reported in this individual (Van Driest et al., 2004). In addition, Chiou et al. (2014) identified this variant in a proband with HCM who also harbored a variant in the MYH7 gene. Segregation data from this family was insufficient to confirm that R286H segregated independently with HCM (Chiou et al., 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the R286H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, the R286H is observed in 16/18472 (0.1%) of individuals from East Asian ancestry in large population cohorts (Lek et al., 2016). Finally, while missense variants in the same residue (R286P, R286C) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined.
Ambry Genetics RCV000245252 SCV000319027 uncertain significance Cardiovascular phenotype 2019-05-15 criteria provided, single submitter clinical testing The p.R286H variant (also known as c.857G>A), located in coding exon 15 of the TNNT2 gene, results from a G to A substitution at nucleotide position 857. The arginine at codon 286 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in numerous individuals with hypertrophic cardiomyopathy (HCM; Van Driest SL et al., Circulation 2003 Jul; 108(4):445-51; Andersen PS et al., Hum. Mutat. 2009 Mar; 30(3):363-70; Berge KE et al., Clin. Genet. 2014 Oct; 86(4):355-60; Chiou KR et al., J Cardiol 2015 Mar; 65(3):250-6; Lopes LR et al., Heart 2015 Feb; 101(4):294-301; Ripoll-Vera T et al., Rev Esp Cardiol (Engl Ed) 2016 Feb; 69(2):149-58). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Although this variant has been reported in multiple individuals with HCM, segregation analysis and studies assessing the functional consequence of the alteration are not available. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV000459071 SCV000541916 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 286 of the TNNT2 protein (p.Arg286His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs141121678, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 27082122, 26507537, 28356264, 25086479, 23711808). ClinVar contains an entry for this variant (Variation ID: 43677). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Blueprint Genetics RCV000223838 SCV000927474 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV001187862 SCV001354764 uncertain significance Cardiomyopathy 2020-01-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148899 SCV000190645 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223838 SCV000280534 uncertain significance not provided 2016-01-28 no assertion criteria provided provider interpretation p.Arg286His (c.857 G>A) in TNNT2 (NM_001001430.1) We re-reviewed this variant on September 2nd, 2014 and again on January 21st, 2015. This variant is difficulty to parse without current understanding of the genome and the genetic basis of HCM. It is more common in Asian individuals unselected for HCM than we would expect for a pathogenic HCM variant. However, there are many cases, suggesting it may be enriched in cases. Notably, there are many non-Asian cases. Given these data, it seems likely that the variant is contributing to HCM in the patient and these other cases. It maybe a modifier or susceptibility factor However, it may not be the primary driver. Until we can better understand the role of variants like this we will consider it a variant of uncertain significance. This variant has been reported in at least 13 unrelated probands with HCM, in addition to this patient. Unfortunately several of this cases are unpublished. Also most of those cases don't have ancestry data available and the majority that do are Asian, like the patient. There is no segregation data on this variant. We have seen this variant one other Asian family with HCM in our center. Van Driest et al (2003) first reported this variant in two unrelated probands with HCM in their American cohort (ancestry not reported). The same group later reported an individual with HCM who had this variant and a variant in MYBPC3, p.Ala833Thr (Van Driest et al 2004). Unfortunately it is unclear if that case is the same as one of the previously reported cases. Andersen et al (2008 (2009 on pubmed)) reported the variant in two unrelated probands with HCM in their Dutch cohort. Ancestry was not reported. Ripoll-Vera et al (2015) reported a total of 5 families with HCM with this variant in their Spanish cohort. This was out of 180 families with hereditary cardiomyopathies, most of them having HCM (total number with HCM not specified). Probands underwent sequencing of MYBPC3, MYH7, TNNT2, TNNI3, and TPM1, One family with this variant also carried Arg326Gln in MYBPC3, which is in ClinVar with an assertion of likely benign or benign by 7 different groups (all concordant). In addition to the proband, three unaffected relatives in three different families carried p.Arg286His. It appears that no affected relatives had genetic testing. They noted a founder effect for one other variant observed in their cohort but did not report whether they assessed possible founder effect for p.Arg286His. Ancestry is not reported, however the cases were ascertained at a hospital in the Balearic Islands, Spain. This report is presumably redundant with their abstract from the 2011 European Society of Cardiology meeting and a thesis available online by Tomas Ripoll Vera). Yang et al (2011) observed the variant in 1 of 100 individuals with HCM in their Chinese cohort (article is in Chinese but an English abstract was reviewed). This is very likely the same case reported in an abstract from the 2011 Annual Congress of the European Cardiac Arrhythmia Society by what appears to be the same group (Wenling et al). The arginine at codon 286 is conserved across species. This is a conservative amino acid change with a polar Arginine replaced with a polar Histidine. In silico analysis with Polyphen predicts the variant to be probably damaging. Another variant at the same codon has been reported in association with HCM (p.Arg286Cys; Richard et al 2003, Miliou et al 2005; no segregation data). Two variants at codon 278 have also been reported in HCM cases (p.Arg278Pro, p.Arg278Cys). The variant was reported online in 7 of 44405 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of January 20th, 2015). Specifically, the variant was observed in 7 of 3196 East Asian individuals (MAF 0.0009387). It was also seen in one European. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The variant was not observed in the following laboratory and published control samples:at least 400 ethnically diverse presumably healthy individuals, about 100 of these are of East Asian descent (Familion); Van Driest et al (2003) did not identify the variant in 100 Caucasian and 100 African American presumably healthy controls; Andersen et al (2003) did not observe the variant in 100 Dutch controls; Yang et al (2011) did not observe it in 200 controls, who were presumably Chinese since the study was done in China.

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