chr19-55151875-G-C

Position:

chr19-55151875-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_000363.5(TNNI3):c.592C>G(p.Leu198Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L198P) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.64

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:

TNNI3 (HGNC:):

TNNI3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 chr19-55151874-A-G is described in Lovd as [Pathogenic].

PP5

Variant 19-55151875-G-C is Pathogenic according to our data. Variant chr19-55151875-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.592C>G	p.Leu198Val	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 linkuse as main transcript	c.592C>G	p.Leu198Val	missense_variant	8/8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

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:

0.00000401

AC:

AN:

249572

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

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:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

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

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2023	This variant disrupts the p.Leu198 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been observed in individuals with TNNI3-related conditions (PMID: 15698845), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 177694). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21839045, 22112859, 25524337, 27532257, 32746448, 33777698). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 198 of the TNNI3 protein (p.Leu198Val). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 07, 2021	The p.Leu198Val variant in TNNI3 has been reported in at least 11 individuals with hypertrophic cardiomyopathy (HCM) and segregated with HCM in 5 affected relatives from 4 families (Maron 2012 PMID: 21839045, Otsuka 2012 PMID: 22112859, Arad 2014 PMID: 25558701, Coppini 2014 PMID: 25524337, Lopes 2013 PMID: 23396983, LMM data, Invitae pers. comm, GeneDx pers. comm.). Some adult relatives of two of these individuals who were heterozygous carriers of this variant were not reported to have HCM, suggesting reduced penetrance (CHEO pers. comm., Invitae pers. comm.). Additionally, this variant has also been identified in a teenager with dilated cardiomyopathy (DCM; no other variants identified at the time of testing) and segregated with disease in 2 affected relatives (1 with HCM and 1 with DCM). It has also been identified in 0.01% (1/10072) of Ashkenazi Jewish chromosomes by gnomAD but was absent from all other populations (http://gnomad.broadinstitute.org). Splice prediction tools suggest the creation of a cryptic 5' splice site; however, this information is not predictive enough to determine pathogenicity. Additional computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM, with possibly reduced penetrance. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM2_Supporting. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 12, 2023

- -

Hypertrophic cardiomyopathy 7

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Feb 02, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. Following criteria are met: 0103 - Gain of function and loss of function are reported mechanisms of disease in this gene. The former is associated with familial restrictive cardiomyopathy 1 (MIM#115210) and hypertrophic cardiomyopathy 7 (MIM#613690), while the latter is associated with dilated cardiomyopathy 1FF (MIM#613286) (PMIDs: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. The recessive form of inheritance is the exception and has only been reported in a small number of families (PMIDs: 15070570, 23270746). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 15607392). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 23270746). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with HCM (PMID: 27532257, 22112859, 28087566, ClinVar). This variant has also been identified in HCM probands with additional variants in other genes (PMID: 33777698, 25558701, 21839045, 23396983). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant segregated with HCM in two affected siblings of a HCM proband (PMID: 22112859). This variant has also been identified in two unaffected daughters of a HCM proband, however, this could be due to incomplete or age-related penetrance (PMID: 25558701). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19914256, 26526134, 19754353, 21839045, 25558701, 23861362, 25351510, 22112859, 28087566, 19033660, 27532257, 25524337, 32746448, 33777698, 37652022, 37089884) -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jul 12, 2017

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2024

The p.L198V variant (also known as c.592C>G), located in coding exon 8 of the TNNI3 gene, results from a C to G substitution at nucleotide position 592. The leucine at codon 198 is replaced by valine, an amino acid with highly similar properties. This variant has been detected in several individuals diagnosed with hypertrophic cardiomyopathy (HCM) and in individuals from HCM cohorts or cohorts referred for HCM genetic testing (Lopes LR et al. Heart, 2015 Feb;101:294-301; Maron BJ et al. Heart Rhythm, 2012 Jan;9:57-63; Otsuka H et al. Circ J, 2012 Nov;76:453-61; Arad M et al. Isr Med Assoc J, 2014 Nov;16:707-13; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Walsh R et al. Genet Med, 2017 02;19:192-203; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476; external communication). This variant has also been reported to segregate with HCM in families (Cava F et al. Mol Genet Metab Rep, 2021 Jun;27:100743; external communication). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this variant is expected to be causative of autosomal dominant cardiomyopathy; however, its clinical significance for autosomal recessive dilated cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

CardioboostCm

Uncertain

0.60

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

0.014

Eigen_PC

Benign

0.016

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.80

N;.

REVEL

Uncertain

0.39

Sift

Benign

0.21

T;.

Sift4G

Benign

0.20

T;T

Polyphen

0.77

P;.

Vest4

0.64

MutPred

0.32

Gain of loop (P = 0.0312);.;

MVP

0.94

MPC

1.1

ClinPred

0.71

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

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.

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