19-55154757-G-T

Position:

chr19-55154757-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000363.5(TNNI3):c.356C>A(p.Thr119Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:15

Conservation

PhyloP100: 0.167

Variant links:

Genes affected

TNNI3 (HGNC:11947): (troponin I3, cardiac type) Troponin I (TnI), along with troponin T (TnT) and troponin C (TnC), is one of 3 subunits that form the troponin complex of the thin filaments of striated muscle. TnI is the inhibitory subunit; blocking actin-myosin interactions and thereby mediating striated muscle relaxation. The TnI subfamily contains three genes: TnI-skeletal-fast-twitch, TnI-skeletal-slow-twitch, and TnI-cardiac. This gene encodes the TnI-cardiac protein and is exclusively expressed in cardiac muscle tissues. Mutations in this gene cause familial hypertrophic cardiomyopathy type 7 (CMH7) and familial restrictive cardiomyopathy (RCM). Troponin I is useful in making a diagnosis of heart failure, and of ischemic heart disease. An elevated level of troponin is also now used as indicator of acute myocardial injury in patients hospitalized with moderate/severe Coronavirus Disease 2019 (COVID-19). Such elevation has also been associated with higher risk of mortality in cardiovascular disease patients hospitalized due to COVID-19. [provided by RefSeq, Aug 2020]

TNNI3 links:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a helix (size 46) in uniprot entity TNNI3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000363.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.356C>A	p.Thr119Asn	missense_variant	6/8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNNI3	ENST00000344887.10 linkuse as main transcript	c.356C>A	p.Thr119Asn	missense_variant	6/8	1	NM_000363.5	ENSP00000341838.5	P19429
ENSG00000267110	ENST00000587871.1 linkuse as main transcript	n.*458C>A		splice_region_variant, non_coding_transcript_exon_variant	9/9	5		ENSP00000473050.1	M0R381
ENSG00000267110	ENST00000587871.1 linkuse as main transcript	n.*458C>A		3_prime_UTR_variant	9/9	5		ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249386

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.000129

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:

0.0000265

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000722

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000644

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2020	The TNNI3 c.356C>A; p.Thr119Asn variant (rs184709702) is reported in the literature in cohort studies of patients affected with dilated and hypertrophic cardiomyopathies (Walsh 2017 and Coppini 2014). This variant is also reported to the ClinVar database as uncertain (Variation ID: 43375). It is also found in the general population with an overall allele frequency of 0.003% (10/280,786 alleles) in the Genome Aggregation Database. The threonine at codon 119 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr119Asn variant is uncertain at this time. References: Coppini et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol. 2014 Dec 23. Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb. Gene statement: Pathogenic variants in TNNI3 are associated with autosomal dominant hypertrophic cardiomyopathy 7 (MIM: 613690), familial restrictive cardiomyopathy 1 (MIM: 115210), dilated cardiomyopathy 1FF (MIM: 613286), and autosomal recessive dilated cardiomyopathy 2A (MIM: 611880). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	Reported in individuals with DCM and HCM referred for genetic testing at GeneDx and in published literature (Lakdawala et al., 2012; Coppini et al., 2014; Pugh et al., 2014; Wang et al., 2016; Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26169204, 27532257, 24503780, 26440512, 22464770, 25524337) -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 08, 2022	This missense variant replaces threonine with asparagine at codon 119 of the TNNI3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25524337). This variant has been identified in 10/280786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces threonine with asparagine at codon 119 of the TNNI3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 25524337, 30297972) and in two individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant has been identified in 10/280786 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2022	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 119 of the TNNI3 protein (p.Thr119Asn). This variant is present in population databases (rs184709702, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 24503780, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 43375). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 09, 2018

Variant summary: TNNI3 c.356C>A (p.Thr119Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277112 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.356C>A, has been reported in the literature in individuals affected with Cardiomyopathy (Walsh_2016, Pugh_2014, Coppini_2014, Lakdawala_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported in our internal database (MYH7 c.2722C>G, p.Leu908Val) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hypertrophic cardiomyopathy 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 18, 2024

- -

Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept of Medical Biology, Uskudar University

Jan 08, 2024

Criteria: PM2, PP2, BP4 -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2019

The p.Thr119Asn variant in TNNI3 has been reported in 2 individuals with DCM and 1 individual with HCM (Coppini 2014, LMM data), but has been identified in 3/24022 of African and 3/126650 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs184709702). Computational prediction tools and conservation analysis suggest that the p.Thr119Asn variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr119Asn variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting; BP4. -

Dilated cardiomyopathy 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 16, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2022

The p.T119N variant (also known as c.356C>A), located in coding exon 6 of the TNNI3 gene, results from a C to A substitution at nucleotide position 356. The threonine at codon 119 is replaced by asparagine, an amino acid with similar properties. This variant was observed in one individual reported to have hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600). This variant was also reported in two individuals with dilated cardiomyopathy (DCM) who also had variants in other cardiac related genes (Pugh TJ et al. Genet Med. 2014;16(8):601-8). This amino acid position is not well conserved in available vertebrate species, and asparagine is the reference amino acid in other 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. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jan 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

CardioboostCm

Benign

0.039

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.56

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

-0.53

N;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

0.010

N;.

REVEL

Pathogenic

0.74

Sift

Benign

0.67

T;.

Sift4G

Benign

0.58

T;T

Polyphen

0.0

B;.

Vest4

0.70

MVP

0.58

MPC

0.75

ClinPred

0.0092

GERP RS

0.58

Varity_R

0.20

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

Other links and lift over