Submissions for variant NM_001276345.2(TNNT2):c.311G>A (p.Arg104His)

dbSNP: rs397516457

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036575	SCV000060230	pathogenic	Hypertrophic cardiomyopathy	2017-06-19	criteria provided, single submitter	clinical testing	The p.Arg94His variant in TNNT2 has been reported in at least 6 individuals with HCM, including 3 de novo occurrences (Ho 2009, Millat 2010, Ripoll-Vera 2016, W alsh 2016, LMM data, ClinVar Variation ID 43628). The variant also segregated wi th disease in 2 affected members of 1 family (Ripoll-Vera 2016), and was absent from large population studies. Arginine (Arg) at position 94 is highly conserved in mammals and across evolutionarily distant species and the change to histidin e (His) was predicted to be pathogenic using a computational tool clinically val idated by our laboratory. This tool's pathogenic prediction is estimated to be c orrect 94% of the time (Jordan 2011). In addition, 2 other likely disease-causin g variants at this position (p.Arg94Cys and p.Arg94Leu) have been reported in mu ltiple individuals with HCM (Varnava 1999, Walsh 2016). In summary, the p.Arg94H is variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner.
GeneDx	RCV000159283	SCV000209229	pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25351510, 25524337, 20624503, 23283745, 11606294, 29398688, 10978365, 27532257, 26507537, 31308319, 31737537, 35653365, 33025817, 32746448, 33906374, 34076677, 35514357, 28566242, 20031602)
Invitae	RCV000230630	SCV000285649	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the TNNT2 protein (p.Arg94His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 2003160, 20624503; Invitae). ClinVar contains an entry for this variant (Variation ID: 43628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 11606294). This variant disrupts the p.Arg94 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10525521, 10978365, 11606294). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000619351	SCV000739953	pathogenic	Cardiovascular phenotype	2022-06-13	criteria provided, single submitter	clinical testing	The p.R94H pathogenic mutation (also known as c.281G>A), located in coding exon 8 of the TNNT2 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by histidine, an amino acid with highly similar properties. This variant was reported in multiple individuals diagnosed with hypertrophic cardiomyopathy (HCM), and co-segregation was observed in three affected relatives from two families (Ho CY et al. Circ Cardiovasc Genet. 2009;2:314-21; Ripoll-Vera T et al. Rev Esp Cardiol (Engl Ed) 2016;69:149-58; Jiménez-Jáimez J et al. Rev Esp Cardiol (Engl Ed), 2017 Oct;70:808-816). This alteration was also detected in one individual diagnosed with HCM in childhood, in whom this variant was noted to occur de novo and in the presence of an alteration in the MYH7 gene (Millat G et al. Eur J Med Genet 2010; 53:261-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is in a functionally important region (motif) and near other pathogenic variants (Palm T et al. Biophys. J., 2001 Nov;81:2827-37; Gangadharan B et al. Proc. Natl. Acad. Sci. U.S.A., 2017 10;114:11115-11120). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV003450684	SCV004181485	pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450685	SCV004181486	pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450683	SCV004181487	pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000036575	SCV004839108	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 94 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 19659763, 20031602, 20624503, 25351510, 26507537, 27532257, 28566242, 31308319, 32746448, 35026164, 35581268, 36357925, 26507537, 28566242). It has been shown that this variant segregates with disease in 3 affected individuals across 2 families (PMID: 26507537, 28566242). In one family, this variant has been reported to occur de novo in an individual affected with hypertrophic cardiomyopathy and with no family history (PMID: 36357925). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg94Cys and p.Arg94Leu, are considered to be disease-causing (ClinVar variation ID: 165549 and 43629), suggesting that arginine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Pathogenic.