rs397516357

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000363.5(TNNI3):c.557G>A(p.Arg186Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,880 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., 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:13

Conservation

PhyloP100: 0.456

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 13 ACMG points.

PM1

In a helix (size 25) in uniprot entity TNNI3_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000363.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

PP5

Variant 19-55151910-C-T is Pathogenic according to our data. Variant chr19-55151910-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55151910-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.557G>A	p.Arg186Gln	missense_variant	Exon 8 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.557G>A	p.Arg186Gln	missense_variant	Exon 8 of 8	1	NM_000363.5	ENSP00000341838.5		P19429

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727148

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 7

Pathogenic:4

Mar 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0004%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.60 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013272 /PMID: 7719344 /3billion dataset). A different missense change at the same codon (p.Ser252Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013279 /PMID: 9002682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 17, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557G>A (p.Arg186Gln) variant in the TNNI3 gene has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 22301726, 23540544, 25524337, 25351510, 26169204, 27532257). This variant is not observed in gnomAD. This variant has been reported to co-segregate with HCM in multiple families with incomplete penetrance (PMID: 15607392, 23540544). This variant has also been reported in patients with HCM by other laboratories. The Arginine 186 is a moderately conserved residue, and multiple algorithms predicted the p.Arg186Gln change to be deleterious. Therefore, the c.557G>A (p.Arg186Gln) variant in the TNNI3 gene is classified as pathogenic. -

Jul 11, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNNI3 c.557G>A (p.Arg186Gln) missense variant has been identified in at least ten individuals with a phenotype consistent with hypertrophic cardiomyopathy (PMID: 12707239; 22301726; 20624503; 27532257; 23540544; 21239446; 25524337; 33906374; 35653365). This variant has been shown to segregate with disease across multiple families (PMID: 15607392; 26169204). The p.Arg186Gln variant is located in a known hotspot region and is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.557G>A (p.Arg186Gln) variant is classified as pathogenic for hypertrophic cardiomyopathy. -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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 arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0710 - Other missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg186Trp) has been reported as likely pathogenic (ClinVar) and VUS (ClinVar, PMID: 35027292) in association with HCM and sudden death. p.(Arg186Gly) has been reported in a family with mixed morphologic features of HCM and left ventricular non-compaction (PMID: 28567093); however, we do not consider it comparable to inform pathogenicity because it has a major Grantham score. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with HCM (ClinVar, PMIDs: 33567718, 33297573, 27532257) and segregated with incomplete penetrance in two families (PMID: 15607392). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy

Pathogenic:3

Mar 19, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg186Gln variant in TNNI3 has been identified in at least 14 individuals with HCM, segregated with disease in 14 affected relatives from 4 families (Rich ard 2004, Mogensen 2004, Millat 2010, Fokstuen 2011, Zhu Hu 2012, Roberts 2013, Wang 2015, Walsh 2016, LMM data). It was absent from large population studies. I n summary, this variant meets our criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon case observations, segregation stud ies and absence from controls. ACMG/AMP Criteria applied: PS4; PP1_Strong; PM2; BP4. -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 186 of the TNNI3 protein (p.Arg186Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 20624503, 21239446, 23540544, 25524337, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43395). 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 disruptive. For these reasons, this variant has been classified as Pathogenic. -

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jan 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15607392, 22301726, 27532257, 21310275, 23540544, 19754353, 15524171, 20624503, 23782526, 26183555, 26199943, 28166811, 27681577, 16020591, 25524337, 12707239, 21239446, 26169204, 28567093, 31513939, 33673806, 33297573, 32746448, 35653365, 35626289, 36136372, 33906374, 36818426, Yuan2023[Article], 37730225, 25351510, Guo2023[article], 30150400, 35208637, 33567718, 36671572) -

Mar 01, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. The patient had HCM genetic testing with the GeneDx laboratory. The test included sequencing of 18 genes associated with HCM: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC, MYL3, MYL2, LAMP2, PRKAG2, GLA, CAV3, MTTG, MTTI, MTTK, MTTQ, TTR, and TNNC1. Results reported on Nov 23rd 2010 showed that a variant associated with disease was identified: p.Arg186Gln (c.557G>A) in the TNNI3 gene. This variant has been reported in multiple cases of HCM. Richard et al (2003) found the p.Arg186Gln variant in one individual with HCM. No segregation data was reported. Mogensen et al (2004) observed the variant in two unrelated families with HCM. Segregation data was not reported separately for each family, however of 11 total genotype positive individuals in both families, 5 had HCM. No other variants have been reported at codon 186, however a variant has been reported with HCM at a nearby codon (p. Lys183Glu (Mogensen et al 2004)). Arginine is highly conserved across species and isoforms at position 186. This variant substitutes a polar, positively charged amino acid (Arg) with a polar, neutral amino acid (Gln). Richard et al (2003) did not identify the variant in 100 presumably healthy controls of unspecified ethnicity and Mogenson et al (2004) did not observe it in 75 presumably healthy individuals, for a total of 175 controls. Based on these data it is very likely that this variant causes cardiomyopathy. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:2

Jul 29, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy

Pathogenic:1

Feb 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Mar 11, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R186Q pathogenic mutation (also known as c.557G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 557. The arginine at codon 186 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) in multiple individuals (Richard P, Circulation 2003 May; 107(17):2227-32; Millat G, Eur J Med Genet 2010; 53(5):261-7; Roberts WC, Am. J. Cardiol. 2013 Jun; 111(12):1818-22; Lopes LR, Heart 2015 Feb; 101(4):294-301). In addition, this alteration has been shown to segregate with disease across two families (Mogensen J, J. Am. Coll. Cardiol. 2004 Dec; 44(12):2315-25; Wang C, Mol. Genet. Genomics 2016 Feb; 291(1):79-92). 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

Benign

0.13

CardioboostCm

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;T

Eigen

Benign

0.085

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

N;.

REVEL

Uncertain

0.47

Sift

Benign

0.43

T;.

Sift4G

Benign

0.39

T;T

Polyphen

0.90

P;.

Vest4

0.76

MutPred

0.70

Loss of MoRF binding (P = 0.0286);.;

MVP

0.92

MPC

1.3

ClinPred

0.85

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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