ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.886C>T (p.Arg296Cys) (rs367785431)

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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,Partners HealthCare Personalized Medicine RCV000036625 SCV000060280 uncertain significance not specified 2020-06-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg286Cys variant in TNNT2 has been reported in 16 individuals with HCM (Richard 2003 PMID 12707239, Miliou 2005 PMID 15958377, Mook 2013 PMID 23785128, Coppini 2014 PMID 25524337, Walsh 2016 PMID 27532257, Ingles 2017 PMID 28408708, Burns 2017 PMID 28790153, Luo 2020 PMID 31941943, Parbhudayal 2020 PMID 32290750, LMM unpublished data), and in 1 individual with sudden death (Zhang 2016 PMID 27707468). Two of these individuals had additional variants in different genes associated with cardiomyopathy. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43676), and has been identified in 0.02% (3/18018) of East Asian and 0.003% (3/109994) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). An odds ratio of 17.97 (95% CI 7.03-45.92, p<0.0001) was calculated using probands reported by our laboratory, probands in the literature, and the data from the gnomAD database. This odds ratio would meet PS4_Supporting criteria as recommended by the ClinGen Cardiomyopathy Expert Panel (Kelly 2018 PMID 29300372); however, in light of additional probands with HCM reported by other clinical laboratories in ClinVar, PS4_Moderate was applied. Computational prediction tools and conservation analysis suggest that the p.Arg286Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg286Cys variant is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PM2_Supporting, PP3.
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 2020-10-29 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 observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239, 15958377, 23785128, 25524337). This variant is also known as p.Arg293Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 43676). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, 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 2018-05-21 criteria provided, single submitter clinical testing The p.R286C variant (also known as c.856C>T), located in coding exon 15 of the TNNT2 gene, results from a C to T substitution at nucleotide position 856. The arginine at codon 286 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant (also known as p.R293C c.877C>T) has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation. 2003;107(17):2227-32; Mook OR et al. J Med Genet. 2013;50(9):614-26; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600). In one family, this variant was described to co-segregate in a first-degree relative with a subclinical form of HCM (Miliou A et al. Heart. 2005;91(7):966-7). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Center for Human Genetics,University of Leuven RCV000768532 SCV000886851 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Genetics and Genomics Program,Sidra Medicine RCV000768532 SCV001434077 likely pathogenic Hypertrophic cardiomyopathy criteria provided, single submitter research

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