Submissions for variant NM_001276345.2(TNNT2):c.460C>T (p.Arg154Trp)

gnomAD frequency: 0.00003  dbSNP: rs483352832

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000612990	SCV000713432	uncertain significance	not specified	2019-06-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg144Trp variant in TNNT2 has been reported in 1 individual with dilated cardiomyopathy and segregated with disease in 4 affected relatives, including 1 obligate carrier (Rani 2014). It has also been identified in 4/30504 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID #132943). An in vitro functional study suggests that this variant may disrupt troponin binding (Gangadharan 2017) and computational prediction tools suggest that it may impact the protein, though this information is not predictive enough to determine pathogenicity.In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria Applied: PS3_Supporting, PP1, PP3.
Invitae	RCV000646060	SCV000767817	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 144 of the TNNT2 protein (p.Arg144Trp). This variant is present in population databases (rs483352832, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 24992688, 36264615). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg154Trp. ClinVar contains an entry for this variant (Variation ID: 132943). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TNNT2 function (PMID: 28973951, 33025817). 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.
Color Diagnostics, LLC DBA Color Health	RCV000777699	SCV000913632	uncertain significance	Cardiomyopathy	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 144 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of this observation is not known. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 24992688, 34213952; ClinVar SCV002025668.1). It has been shown that this variant segregates with disease in 4 affected individuals in one family (PMID: 24992688). This variant has also been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 33297573) and in two individuals affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771, 34853230). This variant has been identified in 8/249866 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777699	SCV001333852	likely pathogenic	Cardiomyopathy	2018-08-20	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001781461	SCV002025668	likely pathogenic	Dilated cardiomyopathy 1D	2020-04-28	criteria provided, single submitter	clinical testing	The heterozygous p.Arg144Trp missense variant identified in TNNT2 has been reported in a South Indian family affected with late-onset familial dilated cardiomyopathy and sudden cardiac death (SCD) [PMID: 24992688]. The variant was detected in four affected family members (one additional obligate carrierdeceasedpatientwhose DNA was not available for analysis) and was absent in eleven unaffected family members [PMID: 24992688]. ClinVar has an entry of this variant [ClinVar ID:132943]. The p.Arg144Trp variant has overall 0.00003 allele frequency in gnomAD database (8 out of 249,866 heterozygous alleles) and 0.00013 allele frequency (4 out of 30,504 heterozygous alleles) in South Asian subpopulation represented in the gnomAD database. The variant affects a moderately conserved residue, is located within functionally important tropomyosin-binding domain (residues ~80-180) and is predicted “deleterious” by multiple in silico prediction tools. In vitro functional experiments suggest that the p.Arg144Trp variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity [PMID: 28973951]. Based on the available evidence, the p.Arg144Trp variant in the TNNT2 gene is assessed as likely pathogenic.
Klaassen Lab, Charite University Medicine Berlin	RCV002055314	SCV002495734	pathogenic	Left ventricular noncompaction cardiomyopathy		criteria provided, single submitter	research
Klaassen Lab, Charite University Medicine Berlin	RCV002055315	SCV002495745	likely pathogenic	Primary dilated cardiomyopathy; Myocarditis		criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV000777699	SCV004819223	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 144 of the TNNT2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of this observation is not known. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 24992688, 34213952; ClinVar SCV002025668.1). It has been shown that this variant segregates with disease in 4 affected individuals in one family (PMID: 24992688). This variant has also been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 33297573) and in two individuals affected with left ventricular noncompaction cardiomyopathy (PMID: 34540771, 34853230). This variant has been identified in 8/249866 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.
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology	RCV000119344	SCV000154241	pathogenic	Dilated cardiomyopathy 1DD		no assertion criteria provided	not provided	Converted during submission to Pathogenic.