19-55151892-C-T

Position:

chr19-55151892-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.575G>A(p.Arg192His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

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:

TNNI3 (HGNC:):

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 chr19-55151893-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

PP5

Variant 19-55151892-C-T is Pathogenic according to our data. Variant chr19-55151892-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55151892-C-T is described in Lovd as [Pathogenic]. Variant chr19-55151892-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 linkuse as main transcript	c.575G>A	p.Arg192His	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.575G>A	p.Arg192His	missense_variant	8/8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000291

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy, familial restrictive, 1

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The missense c.575G>A(p.Arg192His) variant in TNNI3 gene has been reported previously in heterozygous state in multiple individuals affected with restrictive cardiomyopathy (Kohda M, et. al., 2016; Rai TS, et. al., 2009; Mogensen J, et. al., 2003). Experimental studies have shown that this missense change affects TNNI3 function (Liu B, et. al., 2012; Du J, et. al., 2006). The p.Arg192His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg192His in TNNI3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 192 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Gain of function and loss of function are known 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 couple 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 arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 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) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with restrictive cardiomyopathy or hypertrophic cardiomyopathy, often as de novo or likely de novo (ClinVar). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (LABID). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	Not observed in large population cohorts (Lek et al., 2016); Functional studies demonstrate that R192H increases Ca2+ sensitivity compared to wild-type and increases the binding affinity of the thin filament (Gomes et al., 2005; Kobayashi et al., 2006; Liu et al., 2012); Du et al. (2006) demonstrated that transgenic mice harboring the mouse equivalent of R192H exhibit features characteristic of RCM; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic by other clinical laboratories, one of which found this variant to be de novo in two probands with either RCM or HCM (ClinVar Variant ID# 12424; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20617149, 19449150, 31912959, 25611685, 29907873, 12531876, 15961398, 17463320, 18423659, 18408133, 19289050, 20161772, 21310275, 22783303, 21777381, 22675533, 23844019, 25649125, 24474965, 27532257, 31064352, 30279906, 29176140, 16531415, 17027633, 27535533, 26582918, 33673806) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 19, 2021	- -

Restrictive cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 03, 2018

- -

Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2019

The p.Arg192His variant in TNNI3 has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013, LMM data). This variant has not been identified in large population studies. In vitro studies have shown that the p.Arg192His variant impacts protein function (Gomes 2005, Kobayashi 2006, Davis 2007, Mathur 2009, Davis 2010, Liu 2012) and mouse models of this variant develop a restrictive cardiomyopathy phenotype (Du 2006, Du 2008). Finally, other likely disease-causing variants at this position (p.Arg192Cys, p.Arg192Leu) have been identified in individuals with RCM and HCM (Millat 2010, van den Wijngaard 2011, LMM data). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RCM and HCM. ACMG/AMP Criteria applied: PS3, PS4_Moderate, PM6_Strong, PM2, PM5. -

SUDDEN INFANT DEATH SYNDROME

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 08, 2022

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 14, 2022

Experimental studies have shown that this missense change affects TNNI3 function (PMID: 16531415, 17027633, 17463320, 18408133, 18423659, 19289050, 20161772, 22675533). 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12424). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and restrictive cardiomyopathy (PMID: 12531876, 25611685). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 192 of the TNNI3 protein (p.Arg192His). -

Dilated cardiomyopathy 2A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant p.R192H in TNNI3 (NM_000363.5) causes the same amino acid change as a previously established pathogenic variant. The p.Arg192His variant in TNNI3 (NM_000363.5) has been reported in 9 individuals with predominantly childhood onset RCM or HCM and occurred de novo in 4 of these cases (Mogensen 2003, Gomes 2005, Rai 2009, Yang 2013). The p.R192H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The gene TNNI3 contains 38 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 9 variants within 6 amino acid positions of the variant p.R192H have been shown to be pathogenic, while none have been shown to be benign. The p.R192H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 192 of TNNI3 is conserved in all mammalian species. The nucleotide c.575 in TNNI3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 22, 2014

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

The p.R192H pathogenic mutation (also known as c.575G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 575. The arginine at codon 192 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with restrictive cardiomyopathy and/or hypertrophic cardiomyopathy, often with a de novo or likely de novo origin (Mogensen J et al. J. Clin. Invest. 2003;111:209-16; Rai TS et al. Mol. Cell. Biochem. 2009;331:187-92; Alfares AA et al. Genet. Med. 2015;17:880-8; Chen Y et al. J Biomed Res. 2014;28:59-63; Thomas TO et al. Pediatr Transplant. 2015;19:E15-8; Kohda M et al. PLoS Genet. 2016;12:e1005679). Numerous in vitro functional assays, cardiomyocyte cell culture experiments, and mouse models have all indicated that p.R192H results in deficient function of the TNNI3 protein (e.g., Gomes AV et al. J. Biol. Chem. 2005;280:30909-15; Davis J et al. Circ. Res. 2007;100:1494-502; Du J et al. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H2604-13; Liu B et al. PLoS ONE. 2012;7:e38259). In addition, two other alterations associated with RCM and/or HCM, p.R192C and p.R192L, have been described in the same codon (Millat G et al. Clin. Chim. Acta. 2010;411:1983-91; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Alfares AA et al. Genet. Med. 2015;17:880-8). 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

0.92

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.77

MutPred

0.83

Loss of MoRF binding (P = 0.0152);.;

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

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