19-55154146-G-C

Variant names:

• chr19-55154146-G-C
• rs104894724
• NM_000363.5:c.433C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000363.5(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 NM_000363.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.31
• Publications: 113 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• cardiomyopathy, familial restrictive, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy 1FF

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated restrictive cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain 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 chr19-55154145-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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 VariationId is 12419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	NM_000363.5	MANE Select	c.433C>G	p.Arg145Gly	missense	Exon 7 of 8	NP_000354.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNI3	ENST00000344887.10	TSL:1 MANE Select	c.433C>G	p.Arg145Gly	missense	Exon 7 of 8	ENSP00000341838.5
	TNNI3	ENST00000665070.1		c.466C>G	p.Arg156Gly	missense	Exon 7 of 8	ENSP00000499482.1
	TNNI3	ENST00000714238.1		c.421C>G	p.Arg141Gly	missense	Exon 7 of 8	ENSP00000519518.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461034 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726816

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 7 Pathogenic:2

May 06, 2021

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 - 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

Jul 18, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hypertrophic cardiomyopathy Pathogenic:2

Aug 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Jan 31, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Cardiomyopathy Pathogenic:1

Apr 07, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jan 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 21, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0020	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	D
GERP RS		0.79
Varity_R		0.96
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894724; hg19: chr19-55665514;