Submissions for variant NM_001276345.2(TNNT2):c.268C>T (p.Pro90Ser)

dbSNP: rs397516451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036565	SCV000060220	uncertain significance	not specified	2010-11-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The Pro80Ser va riant has not been reported in the literature. Proline (Pro) at position 80 is highly conserved across several evolutionarily distant species. In addition, th is variant was predicted to be pathogenic using a novel computational tool (a cu stomized sarcomere-specific PolyPhen tool, which was validated using a set of ca rdiomyopathy variants with well-established clinical significance). This tool's pathogenic prediction is estimated to be correct 94% of the time, which suggests but does not prove that this variant is pathogenic. However, in the absence of additional supporting data, the clinical significance of this variant cannot be determined at this time.
Invitae	RCV000204383	SCV000260850	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 80 of the TNNT2 protein (p.Pro80Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22112859, 27532257). ClinVar contains an entry for this variant (Variation ID: 43620). 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 does not substantially affect TNNT2 function (PMID: 28973951). 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	RCV000617520	SCV000740221	uncertain significance	Cardiovascular phenotype	2022-07-28	criteria provided, single submitter	clinical testing	The c.238C>T (p.P80S) alteration is located in exon 8 (coding exon 7) of the TNNT2 gene. This alteration results from a C to T substitution at nucleotide position 238, causing the proline (P) at amino acid position 80 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000788418	SCV001790297	uncertain significance	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Reported in association with hypertrophic cardiomyopathy (Otsuka et al., 2012; Walsh et al., 2017); however, specific clinical information was not provided; 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: 22112859, 27532257, 29907873)
Color Diagnostics, LLC DBA Color Health	RCV003531923	SCV004359950	uncertain significance	Cardiomyopathy	2022-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 80 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). A functional study has shown that this variant does not change the affinity of troponin T for tropomyosin in vitro (PMID: 28973951). This variant has been reported in compound heterozygous state with a pathogenic variant in an individual affected with hypertrophic cardiomyopathy of early onset (PMID: 22112859). The proband's mother was an affected heterozygous carrier. This variant has also been reported in another unrelated individual affected with hypertrophic cardiomyopathy (PMID: 27532257). 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.
Blueprint Genetics	RCV000788418	SCV000927518	likely pathogenic	not provided	2018-01-23	flagged submission	clinical testing