19-55154035-C-T

Variant summary

Our verdict is Pathogenic. Variant got 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

2
11
7

Clinical Significance

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

Conservation

PhyloP100: 6.06
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 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 ClinVar as [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 Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNNI3NM_000363.5 linkuse as main transcriptc.544G>A p.Glu182Lys missense_variant 7/8 ENST00000344887.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNNI3ENST00000344887.10 linkuse as main transcriptc.544G>A p.Glu182Lys missense_variant 7/81 NM_000363.5 P1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1459692
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726196
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

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
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 10, 2014The 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. -
Likely pathogenic, no assertion criteria providedclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalOct 12, 2015- -
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioDec 12, 2018- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 25, 2012The 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
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 05, 2022This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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"). ClinVar contains an entry for this variant (Variation ID: 43392). 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. 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). -
Dilated cardiomyopathy 1FF Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenAug 02, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
CardioboostCm
Uncertain
0.43
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T;T
Eigen
Benign
-0.054
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Benign
0.58
N;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
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
D
GERP RS
4.7
Varity_R
0.37

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

LitVar

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

Other links and lift over

dbSNP: rs397516355; hg19: chr19-55665403; API