Submissions for variant NM_001276345.2(TNNT2):c.461G>A (p.Arg154Gln)

gnomAD frequency: 0.00004  dbSNP: rs745632066

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456509	SCV000541910	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-10-13	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 144 of the TNNT2 protein (p.Arg144Gln). This variant is present in population databases (rs745632066, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 404394). 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. This variant disrupts the p.Arg144 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24992688, 28973951, 33025817). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Color Diagnostics, LLC DBA Color Health	RCV001805059	SCV002053036	uncertain significance	Cardiomyopathy	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 144 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 an individual affected with cardiomyopathy (PMID: 29988065). This variant has been identified in 3/249928 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002329016	SCV002627665	uncertain significance	Cardiovascular phenotype	2019-08-30	criteria provided, single submitter	clinical testing	The p.R144Q variant (also known as c.431G>A), located in coding exon 9 of the TNNT2 gene, results from a G to A substitution at nucleotide position 431. The arginine at codon 144 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a cardiomyopathy cohort (Verhagen JMA et al. Eur. J. Hum. Genet., 2018 11;26:1603-1610). Another alteration affecting the same amino acid, p.R144W (c.430C>T), has been reported in association with familial dilated cardiomyopathy (DCM) (Rani DS et al. PLoS ONE, 2014 Jul;9:e101451). This amino acid position is well conserved in available vertebrate species; however, glutamine is the reference amino acid in other 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 alteration remains unclear.
GeneDx	RCV001528223	SCV004023454	uncertain significance	not provided	2023-07-29	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; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV003449114	SCV004181361	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449115	SCV004181363	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449113	SCV004181364	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001805059	SCV004826451	uncertain significance	Cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 144 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 an individual affected with cardiomyopathy (PMID: 29988065). This variant has been identified in 3/249928 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528223	SCV001739594	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001528223	SCV001919005	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528223	SCV001926616	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528223	SCV001952523	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528223	SCV002037743	uncertain significance	not provided		no assertion criteria provided	clinical testing