Submissions for variant NM_001276345.2(TNNT2):c.281G>C (p.Arg94Thr)

dbSNP: rs397516452

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036568	SCV000060223	uncertain significance	not specified	2014-12-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg84Thr variant in TNNT2 has been identified by our laboratory in 2 Asian adults with HC M and segregated with disease in one affected family member. It was absent from large population studies, including a cohort of Asian individuals (http://exac.b roadinstitute.org). Arginine (Arg) at position 84 is conserved in mammals, but n ot in evolutionary distant species. However, the change to threonine (Thr) was p redicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is suspicion for a pathogenic r ole, the clinical significance of the p.Arg84Thr variant is uncertain.
GeneDx	RCV000159277	SCV000209223	uncertain significance	not provided	2020-01-31	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; This variant is associated with the following publications: (PMID: 27532257, 27483260, 31424582)
Ambry Genetics	RCV000244818	SCV000319791	uncertain significance	Cardiovascular phenotype	2019-05-10	criteria provided, single submitter	clinical testing	The c.251G>C (p.R84T) alteration is located in exon 8 (coding exon 7) of the TNNT2 gene. This alteration results from a G to C substitution at nucleotide position 251, causing the arginine (R) at amino acid position 84 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genetics and Genomics Program, Sidra Medicine	RCV001293092	SCV001434075	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366540	SCV001562846	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 84 of the TNNT2 protein (p.Arg84Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27483260, 27532257; Invitae). This variant is also known as c.281G>C (p.Arg94Thr). ClinVar contains an entry for this variant (Variation ID: 43623). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798103	SCV002042843	uncertain significance	Cardiomyopathy	2021-02-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001798103	SCV004359948	uncertain significance	Cardiomyopathy	2022-05-12	criteria provided, single submitter	clinical testing	This missense variant (also known as c.281G>C p.Arg94Thr based on a different transcript NM_001276345.2) replaces arginine with threonine at codon 84 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 been reported in four individuals affected with hypertrophic cardiomyopathy as well as in two unaffected individuals (PMID: 27483260, 27532257, 31424582). This variant has also been reported as de novo in an individual affected with hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome, who also carried a splice variant in the MYBPC3 gene (PMID: 30585570). 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.