chr1-201364341-C-T

Variant names:

• chr1-201364341-C-T
• rs397516466
• NM_001276345.2:c.446G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001276345.2(TNNT2):​c.446G>A​(p.Arg149His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging 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. R149C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 5.91
• Publications: 16 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_001276345.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-201364342-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43640.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 1-201364341-C-T is Pathogenic according to our data. Variant chr1-201364341-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43642.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.446G>A	p.Arg149His	missense_variant	Exon 11 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.446G>A	p.Arg149His	missense_variant	Exon 11 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249998 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726778

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111950

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.000422 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Jun 21, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with DCM referred for genetic testing at GeneDx and in published literature, including some individuals with additional variants in other cardiac related genes (PMID: 27532257, 33906374, 31521807, 20973921); Published functional studies demonstrate a decrease in calcium sensitivity, damaging protein function (PMID: 20973921); 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: 37652022, 20973921, 29367539, 28352236, 21310275, 33019804, 32880476, 24503780, 33500567, 33906374, 31521807, 27532257, 24721642, 35026164) -

Dilated cardiomyopathy 1D Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.446G>A(p.Arg149His) in TNNT2 gene has been reported previously in heterozygous state in individuals with cardiomyopathies (Millat G, et al., 2014, Morales A, et al., 2010). Experimental studies have shown that this missense change affects TNNT2 function (Morales A, et al., 2010). The c.446G>A variant is reported with 0.0004% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic/Uncertain Significance. The variant is predicted to be damaging by SIFT. The amino acid Arginine at position 149 is changed to a Histidine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg149His in TNNT2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Primary dilated cardiomyopathy Pathogenic:1

Feb 07, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg139His variant in TNNT2 has been reported in at least 8 individuals with dilated cardiomyopathy (DCM), including 2 infants, and segregated with disease in at least 8 affected relatives from 2 families. However, this variant has also been found in unaffected relatives (in some individuals in their 50s) and in unaffected parents of infants with DCM (Morales 2010 PMID: 20973921, Millat 2014 PMID: 24721642, Li 2020 PMID: 31521807, Hey 2020 PMID: 33019804, Verdonschot 2020 PMID: 32880476, Ware 2021 PMID: 33906374, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43642) and has been identified in 0.00088% (1/113310) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant impacts protein function (Morales 2010 PMID: 20973921), and computational prediction tools and conservation analyses suggest that this variant may impact the protein. Another variant involving this codon (p.Arg139Cys) has been identified in individuals with DCM. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PM2_Supporting, PP3, PS3_Supporting. -

Cardiovascular phenotype Pathogenic:1

Jan 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R139H variant (also known as c.416G>A), located in coding exon 9 of the TNNT2 gene, results from a G to A substitution at nucleotide position 416. The arginine at codon 139 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in one or more individuals with features consistent with dilated cardiomyopathy (DCM) and segregated with disease in at least one family (Morales A et al. Clin Transl Sci, 2010 Oct;3:219-26; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Li Z et al. Heart Rhythm, 2020 Feb;17:305-312; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 Oct;13:476-487; Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298). Additionally, an in vitro study indicated this alteration may impact calcium sensitization (Morales A et al. Clin Transl Sci, 2010 Oct;3:219-26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Dec 12, 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 histidine, which is basic and polar, at codon 139 of the TNNT2 protein (p.Arg139His). This variant is present in population databases (rs397516466, gnomAD 0.0009%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20973921, 27532257; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43642). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TNNT2 protein function. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 20973921). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Apr 08, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TNNT2 c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 244976 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.416G>A has been reported in the literature in individuals affected with Cardiomyopathy (Morales_2010, Pugh_2014, Walsh_2017). The initial publication by Morales et al (2010), reported the presence of this variant in cis with another intronic TNNT2 variant (c.690-6G>A) that the authors considered to be of unknown significance. However the estimated penetrance of Cardiomyopathy (0.33) due to this variant appears to be lower than expected (0.4), as the variant was also identified in the unaffected offspring of the proband with the same TNNT2 genotype (Morales_2010). Therefore, no conclusions can be drawn from these data. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in measures of maximal force of recovery in addition to desensitization of myofilaments to calcium at pH 6.5. However, the authors conclude that a 20% reduction in maximal force recovery represents a significant finding sufficient to explain the pathophysiology of late onset DCM brought on by fatty inflitration of the right ventricle (Morales_2010). Additional independent confirmation of these functional findings is awaited. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D;.;.;D;.;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;M;.;.;.;.;.;.;.
PhyloP100		5.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.4	D;D;D;.;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;.;D
Polyphen		1.0	.;.;.;.;D;.;.;.;.;.;D;.
Vest4		0.77
MutPred		0.53		.;.;.;.;Loss of MoRF binding (P = 0.4322);.;.;.;.;.;.;Loss of MoRF binding (P = 0.4322);
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.65
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		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: rs397516466; hg19: chr1-201333469; COSMIC: COSV109409962; COSMIC: COSV109409962;