rs397516353

chr19-55154109-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000363.5(TNNI3):c.470C>T(p.Ala157Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,046 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A157A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TNNI3 NM_000363.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.88

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, 13 uncertain in NM_000363.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 19-55154109-G-A is Pathogenic according to our data. Variant chr19-55154109-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55154109-G-A is described in Lovd as [Pathogenic]. Variant chr19-55154109-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5	c.470C>T	p.Ala157Val	missense_variant	7/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10	c.470C>T	p.Ala157Val	missense_variant	7/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461046 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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: 22857948, 26199943, 27532257, 19645627, 21533915, 26506446, 21310275, 25524337, 28166811, 24111713, 25351510, 16335287, 24704860, 23283745, 25239116, 15607392, 12707239, 28971120, 35288587, 34076677, 35653365, 28193612) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 157 of the TNNI3 protein (p.Ala157Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (PMID: 12707239, 15607392, 16335287, 19645627, 21533915, 23283745, 24111713, 24704860, 25239116, 25524337, 26506446, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43388). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 17, 2023	This missense variant replaces alanine with valine at codon 157 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 20 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 19645627, 21533915, 22386593, 22857948, 25524337, 26506446, 27532257, 15607392, 26506446). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). It has been shown that this variant segregates with disease in at least 7 individuals affected with hypertrophic cardiomyopathy across 4 families (PMID: 15607392, 26506446). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 05, 2020	The p.Ala157Val variant in TNNI3 has been reported in > 20 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 7 affected individuals from at least 6 families (Richard 2003 PMID: 12707239; Mogensen 2004 PMID: 15607392; Brito 2005 PMID: 16335287, Curila 2009 PMID: 19645627; van den Wijngaard 2011 PMID: 21533915; Coppini 2014 PMID: 25524337; Walsh 2017 PMID: 27532257; LMM internal data). This variant has also been reported in 2 individuals with sudden death at a young age (van den Wijngaard 2011 PMID: 21533915) and in one individual with DCM (Walsh 2017 PMID: 27532257). Additionally, the p.Ala157Val variant has been reported by other clinical laboratories in ClinVar (Variation ID: 43388) and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting. -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 14, 2022	This missense variant replaces alanine with valine at codon 157 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 20 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 19645627, 21533915, 22386593, 22857948, 25524337, 26506446, 27532257, 15607392, 26506446). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 27532257). It has been shown that this variant segregates with disease in at least 7 individuals affected with hypertrophic cardiomyopathy across 4 families (PMID: 15607392, 26506446). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 23, 2019	- -

TNNI3-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 06, 2023

The TNNI3 c.470C>T variant is predicted to result in the amino acid substitution p.Ala157Val. This variant has been reported in multiple individuals with dilated or hypertrophic cardiomyopathy (see for example - Richard et al. 2003. PubMed ID: 12707239; Table SI - Captur et al. 2014. PubMed ID: 24704860; Table S1A/B - Walsh et al. 2016. PubMed ID: 27532257). Functional studies (Zheng et al. 2015. PubMed ID: 26506446). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted by multiple labs to be likely pathogenic/pathogenic in ClinVar (https://ncbi.nlm.nih.gov/clinvar/variation/43388/). This variant is interpreted as pathogenic. -

Hypertrophic cardiomyopathy 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Nov 08, 2017

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 06, 2020

Variant summary: TNNI3 c.470C>T (p.Ala157Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249082 control chromosomes (gnomAD). c.470C>T has been reported in the literature in several individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Brito_2005, Mogensen_2004, Curila_2009, Zheng_2016, Walsh_2017), and in many families the variant was demonstrated to segregate with the disease, (Richard_2003, Mogensen_2004, Curila_2009, Zheng_2016). The phenotypic manifestations ranged from clinically silent to sudden cardiac death, in addition the variant was also reported in an individual with dilated cardiomyopathy (Walsh_2017); these reports might indicate a variable penetrance. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a decreased level of the TNNI3 protein in a mammalian cell based expression system (Zheng_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2023

The p.A157V variant (also known as c.470C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 470. The alanine at codon 157 is replaced by valine, an amino acid with similar properties. This variant has been previously reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has also been reported to segregate with HCM in families; however, in some cases clinical details or genes analyzed were limited (Richard P et al. Circulation. 2003;107:2227-32; Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25; Brito D et al. Rev Port Cardiol. 2005;24:1137-46; Curila K et al. Genet Test Mol Biomarkers. 2009;13:647-50; van den Wijngaard A et al. Neth Heart J. 2011;19(7-8):344-51; Zou Y et al. Mol Biol Rep. 2013;40(6):3969-76; Berge KE et al. Clin Genet. 2014;86(4):355-60; Captur G. Circ Cardiovasc Genet. 2014;7(3):241-8; Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600; Lopes LR et al. Heart. 2015;101:294-301). In vitro analysis from one study suggested a possible impact to protein expression as a result of this variant (Zheng H et al. Cardiology. 2016;133:91-6). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.016	D;.
Sift4G	Uncertain	0.039	D;D
Polyphen		0.96	D;.
Vest4		0.88
MutPred		0.87		Loss of helix (P = 0.0167);.;
MVP		0.94
MPC		1.7
ClinPred		0.98	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516353; hg19: chr19-55665477; COSMIC: COSV52572392; COSMIC: COSV52572392;