1-201359244-C-G

Variant names:

• chr1-201359244-C-G
• rs397516484
• NM_001276345.2:c.863G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_001276345.2(TNNT2):​c.863G>C​(p.Arg288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: 1.79
• Publications: 19 publications found

Genes affected

TNNT2 (HGNC:11949): (troponin T2, cardiac type) This gene encodes the cardiac isoform of troponin T. The encoded protein is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration. Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with dilated cardiomyopathy. [provided by RefSeq, May 2022]

TNNT2 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1D

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy 3

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• cardiomyopathy, familial restrictive, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000286600 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 21 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-201359244-C-G is Pathogenic according to our data. Variant chr1-201359244-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177635.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38560572). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	NM_001276345.2	MANE Select	c.863G>C	p.Arg288Pro	missense	Exon 17 of 17	NP_001263274.1
	TNNT2	NM_000364.4		c.854G>C	p.Arg285Pro	missense	Exon 16 of 16	NP_000355.2
	TNNT2	NM_001406723.1		c.854G>C	p.Arg285Pro	missense	Exon 16 of 16	NP_001393652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT2	ENST00000656932.1	MANE Select	c.863G>C	p.Arg288Pro	missense	Exon 17 of 17	ENSP00000499593.1
	TNNT2	ENST00000367322.6	TSL:1	c.821G>C	p.Arg274Pro	missense	Exon 15 of 15	ENSP00000356291.2
	TNNT2	ENST00000367320.6	TSL:1	c.734G>C	p.Arg245Pro	missense	Exon 15 of 15	ENSP00000356289.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459070 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725326

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111222

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Pathogenic:2

Jul 27, 2021

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R278P variant (also known as c.833G>C), located in coding exon 15 of the TNNT2 gene, results from a G to C substitution at nucleotide position 833. The arginine at codon 278 is replaced by proline, an amino acid with dissimilar properties. This variant (also referred to as p.R285P, c.854G>C and p.R288P, c.863G>C) was identified in one or more individuals with features consistent with TNNT2-related cardiomyopathy and segregated with disease in at least one family (Van Driest SL et al. Circulation, 2003 Jul;108:445-51; Erdmann J et al. Clin Genet, 2003 Oct;64:339-49; Miliou A et al. Heart, 2005 Jul;91:966-7; Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Liu W et al. Clin Chim Acta, 2021 Sep;520:43-52). In an assay testing TNNT2 function, this variant showed a functionally abnormal result (Lassalle MW. Biosci Biotechnol Biochem, 2010 Jan;74:82-91). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2 Pathogenic:1

Aug 20, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This TNNT2 variant results in the replacement of an arginine with a proline amino acid at codon 278. This variant is not present in the gnomAD population database. It has also been observed in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 12974739, 15958377, 23283745, 24793961). In vitro functional studies suggest this variant affects protein binding (PMID: 20057144). In addition, other variants at this same codon (e.g, p.Arg278His) have also been reported in individuals with HCM. This TNNT2 variant is considered likely pathogenic.

Cardiomyopathy Pathogenic:1

Oct 13, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Oct 06, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Functional studies demonstrated that p.(R278P) alters Troponin binding (PMID: 20057144); In silico analysis suggests that this missense variant does not alter protein structure/function; Also known as p.(R285P); This variant is associated with the following publications: (PMID: 15201162, 34087240, 23283745, 24793961, 12860912, 20031601, 15958377, 27532257, 9154300, 25611685, 34621001, 12974739, 37652022, 35534676, 36243179, 20057144)

Dilated cardiomyopathy 1D;C1861864:Hypertrophic cardiomyopathy 2;C2676271:Cardiomyopathy, familial restrictive, 3 Pathogenic:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 278 of the TNNT2 protein (p.Arg278Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 15958377, 23283745, 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 177635). 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%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20057144). This variant disrupts the p.Arg278 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been observed in individuals with TNNT2-related conditions (PMID: 12974739, 15958377, 23233322, 23283745, 24793961), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Hypertrophic cardiomyopathy 1 Pathogenic:1

Mar 14, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The TNNT2(NM_000364.3: c.854G>C; p.Arg285Pro) variant is reported in literature as TNNT2 (NM_001001430.2:c.833G>C Arg278Pro) and has been reported in multiple cases of HCM and was absent from 200 controls collectively (Zou Y, et al., 2012; Millou A, et al., 2005; Van Driest SL, et al., 2003; Erdmann J, et al., 1998; Abchee A & Marian AJ, 1997). The variant has also been reported to segregate with disease (Abchee A & Marian AJ, 1997; Miliou A, et al., 2005). The variant is absent from both the 1000 genomes project (http://www.1000genomes.org/) and Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease. Interestingly, different rare variants at this position (Arg278Cys and Arg278His) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools PolyPhen-2 and MutationTaster predict this variant to be "probably damaging" and "disease-causing" respectively, however SIFT predicts this variant to be "tolerated", and no prediction is called by PolyPhen-HCM. A functional study on this variant indicated that the TNNT2 Arg278Pro variant alters protein binding, and that any changes within this region of the protein will affect protein function (Lassalle MW, 2010). In summary, multiple unrelated HCM probands reported with the variant, rarity in general populations and functional studies supportive of a damaging effect on function, we have classified the TNNT2 Arg285Pro variant as "Likely Pathogenic".

not specified Uncertain:1

Feb 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.48
Sift	Benign	0.16	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.35
MutPred		0.42		Loss of methylation at R288 (P = 0.0188)
MVP		0.94
MPC		1.7
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.39
gMVP		0.58
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516484; hg19: chr1-201328372;