19-55154146-G-C

Position:

chr19-55154146-G-C

Variant summary

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

The ENST00000344887.10(TNNI3):c.433C>G(p.Arg145Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,034 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. R145Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNNI3
ENST00000344887.10 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.31

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000344887.10

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-55154145-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 19-55154146-G-C is Pathogenic according to our data. Variant chr19-55154146-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154146-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.433C>G	p.Arg145Gly	missense_variant	7/8	ENST00000344887.10	NP_000354.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 linkuse as main transcript	c.433C>G	p.Arg145Gly	missense_variant	7/8	1	NM_000363.5	ENSP00000341838	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726816

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 7

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 18, 2008	- -
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 - Both loss- and gain-of-function are known mechanisms of disease for this gene, where missense have been functionally proven to cause both mechanisms (PMID: 21533915). (I) 0107 - This gene is associated with autosomal dominant disease. Only a single family has been reported with a recessive form of inheritance (PMID 15070570). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 15607392). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD v2 (Highest allele count: 4 heterozygotes, 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) 0600 - Variant is located in the annotated Troponin domain (DECIPHER, PDB, NCBI). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Arg145Gln) and p.(Arg145Trp) have been reported in cardiomyopathy patients (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Several patients with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) have been reported to harbour this variant (ClinVar; PMID: 20641121). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been shown to segregate in a large hypertrophic cardiomyopathy Chinese family with a total of 5 genotyped affecteds (PMID: 20641121). SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro assays demonstrated loss of inhibitory functions towards actin-myosin interactions (PMID: 11801593). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	The p.Arg145Gly variant in TNNI3 has been reported in 3 individuals with HCM and segregated with disease in 10 affected relatives from 2 families (Kimura 1997, Choi 2010, LMM data). This variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg145Gly variant may impact protein function (Elliott 2000, Deng 2001, Kruger 2005, Robinson 2007). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Additionally, two other disease-causing variants have been reported in this codon (p.Arg145Trp, p.Arg145Gln), further suppporting that changes in this codon are not tolerated. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PP1_Strong; PM2; PM5; PS3_Moderate; PP3; PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg145 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16531415, 18423659, 19289050, 19651143, 21533915, 23283745, 27532257, 27557662). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 10806205, 11724573, 11735257, 15718266, 19289050, 22500102, 26391394). 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. ClinVar contains an entry for this variant (Variation ID: 12419). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9241277, 20641121). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 145 of the TNNI3 protein (p.Arg145Gly). -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 07, 2020

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Transgenic mouse model expressing p.(R145G) showed cardiomyocyte disarray, interstitial fibrosis and premature death, as well as increased CA2+ sensitivity (PMID: 11055985); 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: 10806205, 11735257, 11724573, 15718266, 16531415, 17932326, 24418317, 19289050, 22500102, 20161772, 20641121, 9241277, 26391394, 21310275, 25606687, 27532257, 29760186, 28498465, 11801593, 18430738, 34018815, 33407484, 11055985) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2015

The p.R145G pathogenic mutation (also known as c.433C>G), located in coding exon 7 of the TNNI3 gene, results from a C to G substitution at nucleotide position 433. The arginine at codon 145 is replaced by glycine, an amino acid with dissimilar properties. This mutation was reported to co-segregate with hypertrophic cardiomyopathy (HCM), apical hypertrophy, and related features in a large Korean family and was also reported in a Chinese proband with HCM (Kimura et al. Nat Genet. 1997;16(4):379-82; Choi et al. Clin Cardiol. 2010l;33(7):430-8; Zhao Y et al. Biomed Res Int. 2015;2015:561819). In addition, other alterations affecting the same amino acid, p.R145Q (c.434G>A) and p.R145W (c.433C>T), have been reported in association with HCM and restrictive cardiomyopathy (Mogensen et al. J Clin Invest. 2003;111(2):209-16; Mogensen et al. J Am Coll Cardiol. 2004;44(12):2315-25). Furthermore, in vitro studies and transgenic mouse models suggest that this mutation results in slowed rate and reduced ability of cardiac fibers to relax in the absence of calcium (James et al. Circ Res. 2000; 87(9):805-11; Lang et al. J Biol Chem. 2002;277(14):11670-8; Wen et al. J Biol Chem. 2008;283(29):20484-94). Based on the supporting evidence, p.R145G is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.7

D;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0090

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.98

D;.

Vest4

0.80

MutPred

0.93

Loss of helix (P = 0.0376);.;

MVP

0.94

MPC

1.9

ClinPred

0.99

GERP RS

0.79

Varity_R

0.96

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