Submissions for variant NM_001276345.2(TNNT2):c.473G>A (p.Arg158Gln)

gnomAD frequency: 0.00001  dbSNP: rs730881102

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159298	SCV000209244	uncertain significance	not provided	2022-12-20	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: 30565988, 31006259)
Invitae	RCV001361925	SCV001557918	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-31	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 148 of the TNNT2 protein (p.Arg148Gln). 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 variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is also known as R158Q. ClinVar contains an entry for this variant (Variation ID: 181618). 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: 30565988). 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	RCV002326912	SCV002632289	uncertain significance	Cardiovascular phenotype	2022-11-08	criteria provided, single submitter	clinical testing	The p.R148Q variant (also known as c.443G>A), located in coding exon 9 of the TNNT2 gene, results from a G to A substitution at nucleotide position 443. The arginine at codon 148 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Norrish G et al. Circulation, 2019 Jul;140:184-192). 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.
Fulgent Genetics, Fulgent Genetics	RCV001361925	SCV002814562	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-08-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453225	SCV004181352	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453226	SCV004181353	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453224	SCV004181354	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing