Submissions for variant NM_001276345.2(TNNT2):c.452G>A (p.Arg151Gln)

gnomAD frequency: 0.00001  dbSNP: rs730881101

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159297	SCV000209243	likely pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Identified in multiple unrelated patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (Cuenca et al., 2016; Wang et al., 2020); 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: 19466586, 28007021, 26656454, 24367593, 23539503, 21846512, 15769782, 14654368, 11684629, 24992688, 31589614, 26899768, 34350506, 34428338, 30105547, 34135346, 33996946)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768722	SCV000900092	uncertain significance	Cardiomyopathy	2020-11-23	criteria provided, single submitter	clinical testing
Invitae	RCV000796707	SCV000936231	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the TNNT2 protein (p.Arg141Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of arrhythmogenic cardiomyopathy and/or dilated cardiomyopathy (PMID: 19466586, 26899768; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181617). 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%. This variant disrupts the p.Arg141 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11684629, 14654368, 15769782, 21846512, 23539503, 24367593, 24992688, 26656454). 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.
Color Diagnostics, LLC DBA Color Health	RCV000768722	SCV001342179	likely pathogenic	Cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 141 in the tropomyosin binding domain 1 of the TNNT2 protein. Computational prediction tools indicate that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least ten individuals affected with dilated cardiomyopathy (PMID: 26899768, 33996946, 34350506, 36252119; communication with external laboratories: ClinVar SCV000209243.12, SCV000936231.5; Variation ID: 181617); one of these individuals also carried a pathogenic truncation variant the TTN gene (PMID: 26899768). This variant has been shown to segregate with disease in two affected individuals in one family (PMID: 36252119). This variant has also been reported in seven individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 19645627, 22429680, 25524337) and in one individual affected with sudden cardiac death (PMID: 27332903). This variant has been identified in 2/250100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg141Trp, is reported as disease-causing (ClinVar variation ID: 12414), indicating that arginine at this position is important for TNNT2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
3billion	RCV001808433	SCV002058521	likely pathogenic	Hypertrophic cardiomyopathy 2	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TNNT2 related disorder (ClinVar ID: VCV000181617, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012414, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.98, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002326911	SCV002629658	uncertain significance	Cardiovascular phenotype	2022-02-08	criteria provided, single submitter	clinical testing	The p.R141Q variant (also known as c.422G>A), located in coding exon 9 of the TNNT2 gene, results from a G to A substitution at nucleotide position 422. The arginine at codon 141 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in a family with dilated cardiomyopathy (DCM) where the affected individuals also had a co-occurring TTN nonsense variant (Cuenca S et al. J. Heart Lung Transplant., 2016 05;35:625-35). This variant was also detected in a DCM cohort, as well as exome and targeted sequencing cohorts not selected for cardiomyopathy; however details were limited (Rani DS et al. Abstract #311,Genomic Med, 2008 Dec;2:303-30; Kwak SH et al. Exp. Mol. Med., 2017 07;49:e356; (Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51). Another alteration affecting this codon (R141W, c.421C>T) has been reported in association with DCM (Villard E et al. Eur. Heart J. 2005 Apr;26(8):794-803). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319182	SCV003932368	pathogenic	Primary dilated cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000768722	SCV004827753	uncertain significance	Cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 141 of the TNNT2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 26899768, 34350506; communication with external laboratories: ClinVar SCV000209243.12, SCV000936231.5; Variation ID: 181617); one of these individuals also carried a pathogenic truncation variant the TTN gene (PMID: 26899768). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 19645627, 22429680, 25524337). This variant has also been reported in multiple individuals not known to be affected with TNNT2-related disorders (PMID: 28007021, 28706299, 32355288, 34135346) This variant has been identified in 2/250100 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg141Trp, is considered to be disease-causing (ClinVar variation ID: 12414), suggesting that arginine at this position is important for TNNT2 protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.