19-55154035-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_000363.5(TNNI3):c.544G>A(p.Glu182Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E182E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.06

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hypertrophic cardiomyopathy 7
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
cardiomyopathy, familial restrictive, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy 1FF
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
dilated cardiomyopathy
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated restrictive cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

TNNI3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 31 uncertain in NM_000363.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-55154035-C-T is Pathogenic according to our data. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154035-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 43392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.544G>A	p.Glu182Lys	missense_variant	Exon 7 of 8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 link	c.544G>A	p.Glu182Lys	missense_variant	Exon 7 of 8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459692

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726196

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60264

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Pathogenic:2

Oct 12, 2015

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Glu182Lys variant in TNNI3 has been identified by our laboratory as de novo in 1 African American neonate with DCM and 1 Caucasian infant with DCM. In addit ion, it has not been identified in large population studies. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, this variant meets our criteria to be c lassified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon de novo occurrence in multiple cases. -

Cardiomyopathy

Pathogenic:1

Dec 12, 2018

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 25, 2012

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Glu182Lys mutation in the TNNI3 gene has been reported in association with cardiomyopathy (Lakdawala N et al., 2012). Lakdawla et al. reported Glu182Lys occurred de novo in one patient with DCM and it was absent from approximately 400 control samples. Also, the NHLBI ESP Exome Variant Server reports Glu182Lys was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Glu182Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a position that is highly conserved across species. Furthermore, mutations in nearby codons (Lys183Asn, Lys183Glu, Asn185Lys, Arg186Gln) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. In summary, Glu182Lys in the TNNI3 gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s). -

Hypertrophic cardiomyopathy

Pathogenic:1

Jan 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 182 of the TNNI3 protein (p.Glu182Lys). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 22464770, 24503780, 27532257, 32458740). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43392). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1FF

Pathogenic:1

Aug 02, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

CardioboostCm

Uncertain

0.43

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.054

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.088

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

0.58

N;.

PhyloP100

6.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.90

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.36

T;.

Sift4G

Benign

0.41

T;T

Polyphen

0.088

B;.

Vest4

0.79

MutPred

0.49

Gain of MoRF binding (P = 7e-04);.;

MVP

0.97

MPC

0.87

ClinPred

0.85

GERP RS

4.7

Varity_R

0.37

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over