Submissions for variant NM_001276345.2(TNNT2):c.806A>G (p.Tyr269Cys)

dbSNP: rs1553280112

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521498	SCV000618742	uncertain significance	not provided	2017-07-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TNNT2 gene. The Y259C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y259C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, at least one splice prediction algorithm suggests that the Y259C variant may create a cryptic splice donor site at intron 14, which may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.
Invitae	RCV000532750	SCV000646912	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-03-24	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 450191). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 259 of the TNNT2 protein (p.Tyr259Cys).
Fulgent Genetics, Fulgent Genetics	RCV000532750	SCV002778683	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-10-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159672	SCV003866051	uncertain significance	Cardiovascular phenotype	2023-03-15	criteria provided, single submitter	clinical testing	The p.Y259C variant (also known as c.776A>G), located in coding exon 13 of the TNNT2 gene, results from an A to G substitution at nucleotide position 776. The tyrosine at codon 259 is replaced by cysteine, an amino acid with highly dissimilar 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	RCV003449487	SCV004180533	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449488	SCV004180534	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449486	SCV004180535	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing