Submissions for variant NM_001276345.2(TNNT2):c.764C>T (p.Ala255Val)

dbSNP: rs369181536

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154521	SCV000204193	uncertain significance	not specified	2018-04-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000466013	SCV000541911	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 245 of the TNNT2 protein (p.Ala245Val). This variant is present in population databases (rs369181536, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 177873). 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.
GeneDx	RCV000766828	SCV000618573	uncertain significance	not provided	2019-01-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TNNT2 gene. The c.734 C>T (A245V) variant has been previously reported in association with DCM (Bick et al., 2012; Pugh et al., 2014; Walsh et al., 2017). This variant was first reported in a 69 year-old individual from the offspring cohort of Framingham Heart Study who had features of DCM, including an increased left ventricular diastolic diameter and left atrial diameter, and decreased fractional shortening (Bick et al., 2012). Pugh et al. (2014) also reported this variant in a 53 year-old Caucasian female with a clinical diagnosis and family history of DCM, and no history of skeletal myopathy. Additionally, Chanvat et al. (2016) identified c.734 C>T in their cohort of patients with cardiomyopathy or arrhythmia, although further clinical details describing this patient's specific phenotype were not provided. Thus far, no segregation data are available for any of these published cases. Nevertheless, the c.734 C>T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The c.734 C>T substitution is located in exon 14, and may be functionally significant at mRNA or protein level. At the mRNA level, c.734 C>T occurs at a nucleotide that is conserved across species, and in silico splice prediction algorithms predict this variant may create a cryptic splice donor site upstream of the natural splice donor site in intron 14 and may impact gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. At the protein level, A245V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, although this amino acid substitution occurs at a position that is conserved in mammals, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845317	SCV000987359	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183974	SCV001349833	uncertain significance	Cardiomyopathy	2020-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 245 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 24503780). This variant has also been reported in an individual from a cohort of participants that were not pre-selected for a personal or family history of cardiovascular disorders (PMID: 22958901). This variant has been identified in 1/251480 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	RCV002381490	SCV002674970	uncertain significance	Cardiovascular phenotype	2023-06-12	criteria provided, single submitter	clinical testing	The p.A245V variant (also known as c.734C>T), located in coding exon 13 of the TNNT2 gene, results from a C to T substitution at nucleotide position 734. The alanine at codon 245 is replaced by valine, an amino acid with similar properties. This alteration was reported in one individual with dilated cardiomyopathy (DCM) who also had variants in other cardiac-related genes, as well as in a DCM genetic testing cohort with limited clinical information provided (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well conserved in available 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.
All of Us Research Program, National Institutes of Health	RCV001183974	SCV004821973	uncertain significance	Cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000766828	SCV000927758	likely pathogenic	not provided	2018-06-21	flagged submission	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766828	SCV001925094	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766828	SCV001959451	uncertain significance	not provided		no assertion criteria provided	clinical testing