Submissions for variant NM_001276345.2(TNNT2):c.238T>C (p.Phe80Leu)

dbSNP: rs886039053

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000249796	SCV000319838	uncertain significance	Cardiovascular phenotype	2015-07-17	criteria provided, single submitter	clinical testing	The p.F70L variant (also known as c.208T>C), located in coding exon 7 of the TNNT2 gene, results from a T to C substitution at nucleotide position 208. The phenylalanine at codon 70 is replaced by leucine, an amino acid with highly similar properties. This variant has been published in association with hypertrophic cardiomyopathy in one individual on whom clinical details were not provided (Richard P et al., Circulation 2003 May; 107(17):2227-32). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 variant remains unclear.
GeneDx	RCV001582899	SCV001820045	uncertain significance	not provided	2019-04-17	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 264128; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15201162, 15631686, 26183555, 20031601, 12707239)
Genome-Nilou Lab	RCV003454770	SCV004177949	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454771	SCV004177950	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454769	SCV004177951	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532074	SCV004359952	uncertain significance	Cardiomyopathy	2021-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 70 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 hypertrophic cardiomyopathy (PMID: 12707239). This variant has not been identified 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.
Invitae	RCV003765559	SCV004580648	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 70 of the TNNT2 protein (p.Phe70Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239). ClinVar contains an entry for this variant (Variation ID: 264128). 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%. 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.