19-55154145-C-T

Variant summary

Our verdict is Pathogenic. Variant got 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. R145G) 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:15
• Conservation: PhyloP100: 2.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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 NM_000363.5
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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 [Likely_pathogenic]. Clinvar id is 43384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154145-C-T is described in Lovd as [Pathogenic]. Variant chr19-55154145-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.434G>A	p.Arg145Gln	missense_variant	7/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.434G>A	p.Arg145Gln	missense_variant	7/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248984 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135136

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	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. -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Sep 05, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Feb 09, 2017	ACMG score likely pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Apr 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 12, 2021	- -

Cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 24, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 11, 2023	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. -

Hypertrophic cardiomyopathy 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

The variant was co-segregated with Cardiomyopathy, hypertrophic, 7 in multiple affected family members with additional meioses (PMID: 9241277, 15607392, 23283745, 24111713, 25132132, PP1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11735257, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.8, 3CNET: 0.979, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000016, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012419,VCV000012426, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 24, 2021

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 01, 2015

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

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. -

Computational scores

Source: dbNSFP v4.3

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;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0070	D;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

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

Other links and lift over

dbSNP: rs397516349; hg19: chr19-55665513; COSMIC: COSV52572698; COSMIC: COSV52572698;