19-55151856-C-T

Position:

chr19-55151856-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000363.5(TNNI3):c.611G>A(p.Arg204His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 86 pathogenic changes around while only 10 benign (90%) in NM_000363.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-55151857-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 19-55151856-C-T is Pathogenic according to our data. Variant chr19-55151856-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55151856-C-T is described in Lovd as [Pathogenic]. Variant chr19-55151856-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.611G>A	p.Arg204His	missense_variant	8/8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 link	c.611G>A	p.Arg204His	missense_variant	8/8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TNNI3 protein function (PMID:¬†27895589). This variant has been observed to be de novo in an individual affected with¬†restrictive cardiomyopathy¬†(PMID:¬†29176140) and has been reported in several individuals affected with this disease or¬†hypertrophic cardiomyopathy¬†(PMID:¬†20569525,¬†18801787,¬†15698845,¬†27532257).¬†ClinVar contains an entry for this variant (Variation ID: 177679). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 204 of the TNNI3 protein (p.Arg204His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2015	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Feb 09, 2017	ACMG score likely pathogenic -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Functional studies demonstrated that p.(R204H) results in decreased interaction between cardiac troponin I and cardiac troponin C and T (PMID: 15698845, 27895589); 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: 18801787, 27895589, 20617149, 27930701, 27532257, 24322056, 31912959, 16199542, 15698845, 29176140, 20569525, 33906374, 31737537) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 23, 2016	PP3, PM2, PS2, PS3, PS4 -

TNNI3-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2023

The TNNI3 c.611G>A variant is predicted to result in the amino acid substitution p.Arg204His. This variant was reported in the heterozygous state in patients with arrhythmogenic disorders (Additional data, Marschall et al. 2019. PubMed ID: 31737537; Supplemental Tables, Walsh et al. 2017. PubMed ID: 27532257; Parrott et al. 2020. PubMed ID: 31912959; Ware et al. 2021. PubMed ID: 33906374). Functional studies showed that this variant impacts the protein function of Troponin I (Doolan et al. 2005. PubMed ID: 15698845). Of note, another missense variant affecting the same amino acid (p.Arg204Cys) has also been reported to be causative for hypertrophic cardiomyopathy (Ware et al. 2021. PubMed ID: 33906374). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 10, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants functionally proven to cause a loss of function effect by decreasing calcium sensitivity cause dilated cardiomyopathy (DCM). Missense variants functionally proven to cause a gain of function effect by increasing calcium sensitivity cause hypertrophic cardiomyopathy (HCM) (PMID: 21533915). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Only a single family has been reported with a recessive form of inheritance (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 15607392). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 8). (I) 0251 - Variant is heterozygous. (I) 0301 - Variant is absent from gnomAD. (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative missense change at the same residue (p.Arg204Cys) has been reported as pathogenic, and observed in patients with restrictive cardiomyopathy (RCM) and HCM (ClinVar, PMID: 27895589). (SP) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and reported in multiple patients with HCM, RCM and infantile ventricular septal defects (ClinVar, PMID: 27895589, PMID: 31912959, PMID: 20569525). Some of these reports were de novo. (SP) 1002 - Moderate functional evidence supporting abnormal protein function. Analysis of porcine muscle fibres showed this variant results in increased calcium sensitivity and reduced interactions with Troponins C and T (PMID: 27895589). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Aug 26, 2019

This variant has been identified in 1 HCM proband as part of our research program. Family screening identified two additional affected individuals, one family member was diagnosed with HCM and the other with RCM. The variant segregated to both affected family members (2 meiosis). For further information please feel free to contact us. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 13, 2022

The p.R204H pathogenic mutation (also known as c.611G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 611. The arginine at codon 204 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated cases with hypertrophic cardiomyopathy and restrictive cardiomyopathy, including reported de novo occurrences and pediatric-onset disease, and has shown some segregation with disease in families (Doolan A et al. J Mol Cell Cardiol, 2005 Feb;38:387-93; Ingles J et al. J Med Genet, 2005 Oct;42:e59; Gambarin FI et al. Heart, 2008 Oct;94:1257; Parvatiyar MS et al. J Biomed Biotechnol, 2010 Jun;2010:350706; Yang SW et al. Cardiol Young, 2010 Oct;20:574-6; Ding WH et al. Chin Med J (Engl), 2017 Dec;130:2823-2828; Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Walsh R et al. Genet Med, 2017 02;19:192-203; Maurizi N et al. JAMA Cardiol, 2018 06;3:520-525; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Parrott A et al. Am J Med Genet C Semin Med Genet, 2020 03;184:116-123). This variant has been reported to impact protein-protein interactions and calcium sensitivity in in vitro assays (Doolan A et al. J Mol Cell Cardiol, 2005 Feb;38:387-93; Nguyen S et al. Front Physiol, 2016 Nov;7:520). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.4

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.87

Loss of MoRF binding (P = 0.0115);.;

MVP

1.0

MPC

1.9

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

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