1-201365638-A-T

Position:

chr1-201365638-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_001276345.2(TNNT2):c.266T>A(p.Ile89Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNNT2
NM_001276345.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.24

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a chain Troponin T, cardiac muscle (size 296) in uniprot entity TNNT2_HUMAN there are 88 pathogenic changes around while only 9 benign (91%) in NM_001276345.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

PP5

Variant 1-201365638-A-T is Pathogenic according to our data. Variant chr1-201365638-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 12408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201365638-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT2	NM_001276345.2 linkuse as main transcript	c.266T>A	p.Ile89Asn	missense_variant	9/17	ENST00000656932.1	NP_001263274.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT2	ENST00000656932.1 linkuse as main transcript	c.266T>A	p.Ile89Asn	missense_variant	9/17		NM_001276345.2	ENSP00000499593	A2	P45379-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251132

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135722

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 08, 2019	PS3, PS4, PP1_Strong, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); Multiple functional studies suggest that p.(I79N) impacts myofilament calcium sensitivity (Yanaga et al., 1999; Szczesna et al., 2000; Knollman et al., 2001; Miller et al., 2001; Sommese et al., 2013; Wang et al., 2018); 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: 23663841, 11060294, 10617660, 21683708, 24367593, 26914223, 18651846, 21310275, 27532257, 28166811, 7898523, 8205619, 11113119, 22144547, 28241245, 23396983, 28640247, 28615295, 24510615, 11060291, 29217433, 31006259, 33673806, 33025817, 10085122) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 23, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ile79Asn (c.236T>A) in the TNNT2 gene. This variant has been reported in at least one family with HCM and a high burden of sudden death, one family with a range of cardiomyopathy phenotypes, and in one case of sudden cardiac death. Strong segregation data has been reported in both cardiomyopathy kindreds. Thierfelder et al (1994) and Watkins et al (1995) reported a family with 9 affected family members who all had this variant; four of these individuals suffered a sudden cardiac death. One of the individuals who died suddenly and had the variant was a 16 year old male who had normal clinical findings. Varnava et al (2001) reported the variant in a male who died suddenly at 16 years of age and had evidence of HCM on autopsy. They did not provide detailed phenotypic information about that individual. Menon et al (2008) reported a family with RCM, HCM, and DCM; all nine affected family members carried the p.Ile79Asn variant. Disease-associated variants have been reported in neighboring codons (p.Phe77Leu and p.Gly83Lys), indicating the functional significance of this region in the TNNT2 gene. This is a non conservative amino acid change with a nonpolar Isoleucine being replaced with a polar Asparagine. Isoleucine is completely conserved at position 79 in the cardiac troponin T sequence across all vertebrates. Transgenic mice with this variant do not develop cardiac hypertrophy, even with chronic exercise, however they do show increased calcium sensitivity of the ATPase activity and force development in cardiac myofilaments (Miller et al 2001). Knollman et al (2001) further characterized transgenic mice, concluding that the increased myofilament calcium sensitivity increases baseline contractility but leads to cardiac dysfunction during inotropic stimulation. Rust et al (1999) studied the variant in single adult cardiomyocytes and observed impaired expression of the mutant protein and a disabling of cardiac contraction in the submaximal range of myoplasmic calcium concentrations. Lin et al (1996) studied the equivalent variant in rats and found 50% faster thin filament movement over a surface coated with heavy meromyosin. The variant has also been found to decrease the calcium sensitivity of force production and increase the unloaded shortening velocity (Sweeney et al 1998). Palm et al (2001) found that p.Ile79Asn does not affect tropomyosin binding while variants in resides 92-110 do. Some authors have suggested that this variant and other variants in TNNT2 confer a greater risk of sudden cardiac death with less or even no hypertrophy (Watkins et al 1995; Varnava et al 2001). Certainly the family reported by Thierfelder et al (1994) and then Watkins et al (1995) had multiple cases of sudden death, several with little or no hypertrophy. However, the family reported by Menon et al (2008) had no cases of sudden death or ventricular arrhythmias. In total the variant has not been seen in ~6890 published controls and individuals from publicly available population datasets. There is no variation at codon 79 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of January 30th, 2013). The variant is listed in dbSNP and 1000 genomes but ony in reference to the OMIM entry (rs121964855) (as of January 30th, 2013). The variant was not observed in the following published control samples: Thierfelder et al (1994) did not observe the variant in 100 presumably healthy controls whose race is unspecified. Varnava et al (2001) did not find the variant in 90 controls whose ethnicity is unknown. The testing lab did not detect the va -

Hypertrophic cardiomyopathy 2

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Dilated cardiomyopathy 1D

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Cardiomyopathy, familial restrictive, 3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 18, 2017

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2022

The p.Ile79Asn variant in TNNT2 has been reported in >10 individuals with HCM and segregated with disease in >15 affected relatives from two families (Thierfelder 1994 PMID: 8205619, Watkins 1995 PMID: 7898523, Varnava 2001 PMID: 11560853, Menon 2008 PMID: 18651846, Murphy 2016 PMID: 26914223, Walsh 201 PMID:27532257, LMM data). This variant has also been identified in 0.001% (1/68028) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). In vitro functional studies and animal models suggest that the p.Ile79Asn variant may impact protein function (Yanaga 1999 PMID: 10085122, Miller 2001 PMID: 11060294, Knollmann 2001 PMID: 11113119) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Strong, PM2_Supporting, PS3_Moderate, PP3. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2022

The p.I79N pathogenic mutation (also known as c.236T>A), located in coding exon 7 of the TNNT2 gene, results from a T to A substitution at nucleotide position 236. The isoleucine at codon 79 is replaced by asparagine, an amino acid with dissimilar properties. This mutation has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy and/or sudden cardiac death, and has been shown to segregate with disease in families (Thierfelder L et al. Cell 1994;77(5):701-12; Watkins HN et al. Engl J Med. 1995;332(16):1058-64; Varnava AM et al. Circulation 2001;104(12):1380-4). In one family, this mutation was identified in members with variable presentations, including features of hypertrophic, restrictive, or dilated cardiomyopathy (Menon SC et al. Clin Genet. 2008;74(5):445-54). Multiple in vitro functional studies and mice models have demonstrated abnormal protein function with altered calcium sensitivity, impairment of the inhibitory action of troponin I, and enhanced contractility of cardiac muscle (Yanaga F et al. J Biol Chem. 1999;274(13):8806-12; Szczesna D et al. J Biol Chem. 2000;275(1):624-30; Miller T et al. J Biol Chem. 2001;276(6):3743-55; Knollmann BC. J Biol Chem. 2001;276(13):10039-48; Sommese RF et al. PLoS ONE. 2013;8(12):e83403). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 79 of the TNNT2 protein (p.Ile79Asn). This variant is present in population databases (rs121964855, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8205619, 18651846, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12408). 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 have shown that this missense change affects TNNT2 function (PMID: 10085122, 10617660, 11060291, 11113119, 21683708, 23663841). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

.;.;.;.;D;.;.;.;.;.;D;.;.;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

.;D;D;D;D;D;D;.;.;D;.;.;D;.

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

.;.;.;.;M;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.3

D;D;.;.;.;.;.;.;D;D;D;D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;.;.;.;.;.;.;D;D;D;D;D;D

Sift4G

Benign

0.087

T;T;T;D;D;D;D;D;D;T;.;T;T;.

Polyphen

1.0

.;.;.;.;D;.;.;.;.;.;D;.;.;.

Vest4

0.86

MutPred

0.17

.;.;.;.;Gain of glycosylation at P87 (P = 0.0546);.;.;.;.;.;.;Gain of glycosylation at P87 (P = 0.0546);.;.;

MVP

0.98

MPC

1.9

ClinPred

0.99

GERP RS

4.7

Varity_R

0.44

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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