Submissions for variant NM_001276345.2(TNNT2):c.863G>A (p.Arg288His)

gnomAD frequency: 0.00005  dbSNP: rs397516484

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000201870	SCV000060278	uncertain significance	Hypertrophic cardiomyopathy	2019-04-04	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in two probands with HCM (Pasquale 2012, Burns 2017). Gnomad: 0.01% (3 alleles). Clinvar: VUS (Agnes Ginges). Three other variants at this position are reported in HGMD.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036484	SCV001199851	likely pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-11-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 278 of the TNNT2 protein (p.Arg278His). This variant is present in population databases (rs397516484, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20624503, 22144547, 27532257, 28408708, 33297573). This variant is also known as p.Arg288His. ClinVar contains an entry for this variant (Variation ID: 43674). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TNNT2 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg278 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 15958377, 23283745, 24793961). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV001177680	SCV001341933	uncertain significance	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 278 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in seven unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 22144547, 27532257, 28408708, 28771489, 28790153, 28971120 , 28971120, 33297573). This variant has also been reported in a family affected with hypertrophic cardiomyopathy including two affected carriers and one unaffected carrier (PMID: 34087240). This variant has been identified in 4/275756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg278Pro, is considered to be disease-causing (ClinVar variation ID: 177635), suggesting that arginine at this position is important for TNNT2 protein function. 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	RCV001177680	SCV002042859	uncertain significance	Cardiomyopathy	2021-05-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001036484	SCV002803962	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2021-12-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162317	SCV003866029	uncertain significance	Cardiovascular phenotype	2019-04-15	criteria provided, single submitter	clinical testing	The c.833G>A (p.R278H) alteration is located in exon 16 (coding exon 15) of the TNNT2 gene. This alteration results from a G to A substitution at nucleotide position 833, causing the arginine (R) at amino acid position 278 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV003450724	SCV004180499	uncertain significance	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450725	SCV004180500	uncertain significance	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450723	SCV004180501	uncertain significance	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001699106	SCV004224768	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing	PM5, PS4_moderate
All of Us Research Program, National Institutes of Health	RCV001177680	SCV004833003	uncertain significance	Cardiomyopathy	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 278 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in seven unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 22144547, 27532257, 28408708, 28771489, 28790153, 28971120 , 28971120, 33297573). This variant has also been reported in a family affected with hypertrophic cardiomyopathy including two affected carriers and one unaffected carrier (PMID: 34087240). This variant has been identified in 4/275756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg278Pro, is considered to be disease-causing (ClinVar variation ID: 177635), suggesting that arginine at this position is important for TNNT2 protein function. 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.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000201870	SCV000256639	uncertain significance	Hypertrophic cardiomyopathy	2019-11-26	no assertion criteria provided	research	This TNNT2 Arg278His variant has been reported in 3 HCM probands (Pasquale F, et al., 2012; Walsh R et al., 2017). This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified TNNT2 Arg278His in a proband with HCM, but no family history of disease or sudden cardiac death (Ingles et al., 2017). The proband also carries 2 other variants (TNNT2 c.571-7G>A & MYH7 c.1000-7C>T). Interestingly, different rare variants at this position (Arg278Cys and Arg278Pro) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), the variant is rare in the general population (PM2), has been identified in 4 HCM probands and in silico tools predict the variant to be deleterious, therefore we classify TNNT2 Arg278His as a variant of "uncertain significance".
Clinical Genetics, Academic Medical Center	RCV001699106	SCV001919446	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699106	SCV001967866	uncertain significance	not provided		no assertion criteria provided	clinical testing