rs267607128

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000363.5(TNNI3):c.61C>T(p.Arg21Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.96

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:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Troponin I, cardiac muscle (size 208) in uniprot entity TNNI3_HUMAN there are 86 pathogenic changes around while only 10 benign (90%) in NM_000363.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 19-55157097-G-A is Pathogenic according to our data. Variant chr19-55157097-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55157097-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.61C>T	p.Arg21Cys	missense_variant	Exon 3 of 8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNNI3	ENST00000344887.10 link	c.61C>T	p.Arg21Cys	missense_variant	Exon 3 of 8	1	NM_000363.5	ENSP00000341838.5	P19429
ENSG00000267110	ENST00000587871.1 link	n.*163C>T		non_coding_transcript_exon_variant	Exon 6 of 9	5		ENSP00000473050.1	M0R381
ENSG00000267110	ENST00000587871.1 link	n.*163C>T		3_prime_UTR_variant	Exon 6 of 9	5		ENSP00000473050.1	M0R381

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450698

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720350

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 7

Pathogenic:1

Nov 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Nov 18, 2024

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 cysteine, which is neutral and slightly polar, at codon 21 of the TNNI3 protein (p.Arg21Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 16267253, 24111713, 31737537, 32885985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12434). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 22086914, 25961037, 26391394). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Mar 01, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R21C variant (also known as c.61C>T), located in coding exon 3 of the TNNI3 gene, results from a C to T substitution at nucleotide position 61. The arginine at codon 21 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts (Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Fahed AC et al. Circ Genom Precis Med, 2020 Oct;13:444-452), and it has been found to segregate with HCM and sudden cardiac death among multiple unrelated South Lebanese families (Fahed AC et al. Circ Genom Precis Med, 2020 Oct;13:444-452). Additionally, functional studies show that this alteration impacts protein function by altering phosphorylation and calcium sensitivity, which may lead to the development of a cardiomyopathy phenotype (Gomes AV et al. J Mol Cell Cardiol, 2005 Nov;39:754-65; Wang Y et al. J Biol Chem, 2012 Jan;287:2156-67; Dweck D et al. J Biol Chem, 2014 Aug;289:23097-111; Cheng Y et al. J Biol Chem, 2015 Nov;290:27749-66; Liang J et al. Biomed Res Int, 2015 Apr;2015:742536). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

CardioboostCm

Benign

0.011

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

0.97

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.81

MutPred

0.77

Loss of MoRF binding (P = 0.0123);

MVP

0.94

MPC

0.89

ClinPred

0.78

GERP RS

4.0

Varity_R

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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