19-55154158-G-A

Position:

chr19-55154158-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_000363.5(TNNI3):c.421C>T(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,882 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 0.403

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000363.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-55154157-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 19-55154158-G-A is Pathogenic according to our data. Variant chr19-55154158-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181580.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3}. Variant chr19-55154158-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNI3	NM_000363.5 linkuse as main transcript	c.421C>T	p.Arg141Trp	missense_variant	7/8	ENST00000344887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNI3	ENST00000344887.10 linkuse as main transcript	c.421C>T	p.Arg141Trp	missense_variant	7/8	1	NM_000363.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248702

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135006

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460882

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726752

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:

0.00000629

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 08, 2022	This missense variant replaces arginine with tryptophan at codon 141 of the TNNI3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 29121657). This variant has been identified in 2/248702 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg141Gln, has been associated with hypertrophic cardiomyopathy (Clinvar variation ID: 43381), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 25, 2023	- -

Hypertrophic cardiomyopathy 7

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

Feb 23, 2023

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TNNI3 related disorder (ClinVar ID: VCV000181580). A different missense change at the same codon (p.Arg141Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043381). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2024

Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in the published literature (PMID: 29121657, 30847666); 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: 30847666, 32758068, 29121657) -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 141 of the TNNI3 protein (p.Arg141Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with TNNI3-related conditions (PMID: 29121657, 30847666, 32758068). ClinVar contains an entry for this variant (Variation ID: 181580). 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. This variant disrupts the p.Arg141 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 15607392, 18403758, 19645627, 22429680, 22876777, 23283745, 25524337). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The p.R141W variant (also known as c.421C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 421. The arginine at codon 141 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in one individual with hypertrophic cardiomyopathy (HCM) and in a genetic testing cohort with limited clinical details (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). In addition, a different alteration located at the same position, p.R141Q, has been detected in several individuals with hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation. 2003;107:2227-32; Van Driest SL et al. Circulation. 2003;108:445-51; van den Wijngaard A et al. Neth Heart J. 2011;19:344-51; Rani DS et al. BMC Med. Genet. 2012;13:69; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Landry CH et al. N Engl J Med. 2017;377(20):1943-1953; Curila K et al. Genet Test Mol Biomarkers. 2009;13:647-50), was detected in the homozygous state in an individual with severe biventricular hypertrophy (Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25), has co-occurred with other variants in cardiac-related genes in affected individuals (Morita H et al. N Engl J Med. 2008;358:1899-908; Santos S et al. BMC Med Genet. 2012;13:17), and has been detected in unaffected relatives (Mogensen J et al. J Am Coll Cardiol. 2004;44:2315-25). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of the p.R141W alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.38

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.9

M;.

MutationTaster

Benign

0.84

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.6

D;.

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.74

MutPred

0.80

Loss of disorder (P = 0.0155);.;

MVP

0.96

MPC

1.7

ClinPred

0.99

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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