19-55154145-C-T

Variant names:

• chr19-55154145-C-T
• rs397516349
• NM_000363.5:c.434G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000363.5(TNNI3):​c.434G>A​(p.Arg145Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,164 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 2.30
• Publications: 37 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 16 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-55154146-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 19-55154145-C-T is Pathogenic according to our data. 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.

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.434G>A	p.Arg145Gln	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.434G>A	p.Arg145Gln	missense	Exon 7 of 8	ENSP00000341838.5
	TNNI3	ENST00000665070.1		c.467G>A	p.Arg156Gln	missense	Exon 7 of 8	ENSP00000499482.1
	TNNI3	ENST00000714238.1		c.422G>A	p.Arg141Gln	missense	Exon 7 of 8	ENSP00000519518.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248984 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461164 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 726882

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000289 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 7 Pathogenic:4

Feb 06, 2025

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 v4.1.0 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11735257). 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: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043384 /PMID: 9241277 /3billion dataset). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 15607392, 23283745, 24111713, 25132132, 9241277). Different missense changes at the same codon (p.Arg145Gly, p.Arg145Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012419, VCV000012426 /PMID: 12531876, 9241277 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Sep 05, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.

Oct 04, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TNNI3 c.434G>A p.(Arg145Gln) missense variant results in the substitution of arginine at position 145 with glutamine. This variant has been previously identified in multiple individuals with hypertrophic cardiomyopathy (PMID: 9241277; 15607392; 24111713; 29255176; 33673806). Additionally, two different amino acid substitutions at this same codon have been reported in individuals with hypertrophic cardiomyopathy. Functional studies conduced using purified proteins and in an ex vivo animal model demonstrated that this variant impacts protein function (PMID: 11735257). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.434G>A p.(Arg145Gln) variant has been classified as pathogenic for TNNI3-related cardiomyopathy.

Dec 30, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v2: 4 heterozygotes, 0 homozygotes); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in over ten individuals, the majority of whom are affected with HCM (ClinVar, LOVD, cardiodb.org, PMIDs: 29255176, 9241277, 15607392); Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to glutamine; This variant is heterozygous; 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); An alternative amino acid change at the same position has been observed in gnomAD (v3) (3 heterozygotes, 0 homozygotes); No comparable missense variants have previous evidence for pathogenicity. However, two alternative changes with a stronger Grantham change, p.(Arg145Gly) and p.(Arg145Trp), are submitted as pathogenic in ClinVar; Variant is located in the annotated troponin domain (DECIPHER); 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); The condition associated with this gene has incomplete penetrance (PMIDs: 15607392, 32731933); Variants in this gene are known to have variable expressivity (PMID: 23270746); Inheritance information for this variant is not currently available in this individual.

Hypertrophic cardiomyopathy Pathogenic:4

Jan 15, 2025

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 145 of the TNNI3 protein (p.Arg145Gln). This variant is present in population databases (rs397516349, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (HCM) (PMID: 9241277, 15607392, 23283745, 24111713, 25132132). ClinVar contains an entry for this variant (Variation ID: 43384). An algorithm developed specifically for the TNNI3 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). Experimental studies have shown that this missense change affects TNNI3 function (PMID: 11735257). 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: 11735257, 20641121, 23610579). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg145Gln variant in TNNI3 has been reported in 10 individuals with HCM and 1 individual with RCM who also carried a second variant in TNNI3 (Berge 2014, Mogensen 2004, Kimura 1997, van den Wijngaard 2011, Wang 2014, Zou 2013, LMM data). This variant has also been reported in ClinVar (Variation ID 43384) as Pathogenic and Likely pathogenic, and in 2/17246 East Asian and 2/33578 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516349). 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). In vitro functional studies provide some evidence that the p.Arg145Gln variant may impact protein function (Takahashi-Yanaga 2001). However, these types of assays may not accurately represent biological function. In addition, 2 other pathogenic variants have been reported at this amino acid position (p.Arg145Gly and p.Arg145Trp), suggesting that this residue has functional importance. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg145Gln variant is likely pathogenic.

Feb 09, 2017

Center for Human Genetics, University of Leuven

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG score likely pathogenic

Sep 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 145 in the actin binding region of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant reduces the intrinsic inhibitory activity of the cardiac troponin I protein without changing the apparent affinity for actin and increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 11735257). This variant has been reported in over 15 individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, 27532257, 28193612, 29255176, 32492895, 32686758, 34137518). In one family, it has been shown that this variant segregates with disease in three individuals affected with hypertrophic cardiomyopathy (PMID: 29255176). This variant has also been reported in individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537, 33673806) and in an individual affected with restrictive cardiomyopathy (PMID: 21533915). This variant has been identified in 4/248984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg145Trp and p.Arg145Gly, are considered to be disease-causing (ClinVar variation ID: 12426 and 12419), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

not provided Pathogenic:3

Oct 20, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Described as mosaic in an individual with restrictive cardiomyopathy who also harbored a second missense variant in the TNNI3 gene (van den Wijngaard et al., 2011); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated that R145Q results in a large increase in the Ca2+ sensitivity of cardiac muscle contraction (Takahashi-Yanaga et al., 2001); Reported in ClinVar (ClinVar Variant ID# 43384; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 25132132, 21533915, 23283745, 15961398, 15607392, 24111713, 29203298, 28193612, 9241277, 16288990, 31513939, 31737537, 33673806, 32686758, 34137518, 11735257)

Oct 12, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiomyopathy Pathogenic:2

Dec 24, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 21, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 145 of the TNNI3 protein. This variant is found within a highly conserved region of the actin binding region (aa137-148). Missense variants in this region have been shown to be significantly overrepresented in individuals with affected with hypertrophic cardiomyopathy (PMID: 30696458). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. An experimental functional study has shown that this variant reduces the intrinsic inhibitory activity of the cardiac troponin I protein without changing the apparent affinity for actin and increases the Ca2+ sensitivity of cardiac muscle contraction (PMID: 11735257). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, 27532257, 28193612, 29255176, 32492895, 32686758, 34137518, 35653365, 36291626, 37949661, 38757491). In one family, it has been shown that this variant segregates with disease in three individuals affected with hypertrophic cardiomyopathy (PMID: 29255176). This variant has also been reported in individuals suspected to be affected with hypertrophic cardiomyopathy (PMID: 31737537, 33673806) and in an individual affected with restrictive cardiomyopathy (PMID: 21533915). This variant has been identified in 4/248984 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg145Trp and p.Arg145Gly, are considered to be disease-causing (ClinVar variation ID: 12426 and 12419), suggesting that arginine at this position is important for TNNI3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

Cardiovascular phenotype Pathogenic:2

May 18, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R145Q variant (also known as c.434G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 434. The arginine at codon 145 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM), although in some cases it co-occurred with alterations in TNNI3 or other cardiac-related genes (Kimura A et al. Nat Genet. 1997;16:379-82; Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Berge KE et al. Clin Genet. 2014;86:355-60; Wang J et al. Eur J Heart Fail. 2014;16:950-7; Kim HY et al. J Clin Med, 2020 Jun;9:[Epub ahead of print]). This variant was reported to co-segregate with disease in two families, including one family with a pair of apparently homozygous affected siblings (Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; Al-Shafai KN et al. Mol Genet Genomic Med, 2021 Jul;9:e1709). In vitro functional studies indicate this alteration results in reduced intrinsic inhibitory activity, increased calcium sensitivity of myofibrillar ATPase activity and increased force generation of skinned muscle fibers (Takahashi-Yanaga F et al. J Mol Cell Cardiol. 2001;33:2095-107). This amino acid position is 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 TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is unclear.

Aug 29, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3

Hypertrophic cardiomyopathy 7;C1861861:Cardiomyopathy, familial restrictive, 1;C2678474:Dilated cardiomyopathy 2A;C2750091:Dilated cardiomyopathy 1FF Pathogenic:1

Nov 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Dec 01, 2015

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.94		Loss of catalytic residue at R145 (P = 0.0605)
MVP		0.95
MPC		1.8
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
Mutation Taster		=8/92	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: rs397516349; hg19: chr19-55665513; COSMIC: COSV52572698; COSMIC: COSV52572698;