1-201359636-C-T

Variant names:

• chr1-201359636-C-T
• rs121964861
• NM_001276345.2:c.838G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_001276345.2(TNNT2):​c.838G>A​(p.Asp280Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,446,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D280Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TNNT2 NM_001276345.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:6
• Conservation: PhyloP100: 2.48
• Publications: 18 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 2 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, 12 uncertain in NM_001276345.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT2	NM_001276345.2	c.838G>A	p.Asp280Asn	missense_variant	Exon 16 of 17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1	c.838G>A	p.Asp280Asn	missense_variant	Exon 16 of 17		NM_001276345.2	ENSP00000499593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1446600 Hom.: 0 Cov.: 32 AF XY: 0.00000418 AC XY: 3 AN XY: 717978

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 43266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39282

South Asian (SAS) AF: 0.00 AC: 0 AN: 83846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1103220

Other (OTH) AF: 0.00 AC: 0 AN: 59804

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1D Pathogenic:1 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiomyopathy Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy, familial restrictive, 3 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 2 Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jun 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D270N variant (also known as c.808G>A), located in coding exon 14 of the TNNT2 gene, results from a G to A substitution at nucleotide position 808. The aspartic acid at codon 270 is replaced by asparagine, an amino acid with highly similar properties. This variant has been detected in two affected individuals from a family with dilated cardiomyopathy (Mogensen J et al. J Am Coll Cardiol, 2004 Nov;44:2033-40). In vitro functional assays have indicated this variant may result in decreased calcium sensitivity of myofilaments, impaired protein-protein interactions, and/or reduced cooperativity of calcium binding; however, the precise physiological relevance of these findings is unclear (Mogensen J et al. J Am Coll Cardiol, 2004 Nov;44:2033-40; Mirza M et al. J Biol Chem, 2005 Aug;280:28498-506; Robinson P et al. Circ Res, 2007 Dec;101:1266-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 270 of the TNNT2 protein (p.Asp270Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 15542288). ClinVar contains an entry for this variant (Variation ID: 12417). 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: 15542288, 15923195, 17932326). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
CardioboostCm	Uncertain	0.34
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	.;.;.;.;D;.;.;.;.;.;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;.;.;D;.
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.;.;.;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.8	N;N;.;.;.;.;.;.;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.043	D;D;.;.;.;.;.;.;D;D;T
Sift4G	Benign	0.12	T;T;T;D;T;T;T;T;D;T;.
Polyphen		0.97	.;.;.;.;D;.;.;.;.;.;.
Vest4		0.71
MutPred		0.48		.;.;.;.;Gain of methylation at K283 (P = 0.0632);.;.;.;.;.;.;
MVP		0.95
MPC		1.3
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.80
gMVP		0.77
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs121964861; hg19: chr1-201328764;