Submissions for variant NM_001276345.2(TNNT2):c.706G>A (p.Glu236Lys)

gnomAD frequency: 0.00004  dbSNP: rs730881107

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159309	SCV000209255	uncertain significance	not provided	2021-05-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 181626; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Invitae	RCV000540890	SCV000646907	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-08-09	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 181626). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 226 of the TNNT2 protein (p.Glu226Lys). This variant is present in population databases (rs730881107, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions.
Color Diagnostics, LLC DBA Color Health	RCV001189392	SCV001356675	uncertain significance	Cardiomyopathy	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 226 of the TNNT2 protein. Computational prediction suggests that this variant may have 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/31392 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	RCV002362845	SCV002666516	uncertain significance	Cardiovascular phenotype	2022-02-22	criteria provided, single submitter	clinical testing	The p.E226K variant (also known as c.676G>A), located in coding exon 12 of the TNNT2 gene, results from a G to A substitution at nucleotide position 676. The glutamic acid at codon 226 is replaced by lysine, an amino acid with similar properties. 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.
Genome-Nilou Lab	RCV003453234	SCV004181251	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453235	SCV004181252	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003453233	SCV004181253	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001189392	SCV004821975	uncertain significance	Cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 226 of the TNNT2 protein. Computational prediction suggests that this variant may have 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/31392 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.