rs397516345

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000363.5(TNNI3):c.368C>T(p.Thr123Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TNNI3
NM_000363.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.216

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a helix (size 46) in uniprot entity TNNI3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000363.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNI3	NM_000363.5 link	c.368C>T	p.Thr123Met	missense_variant	Exon 6 of 8	ENST00000344887.10	NP_000354.4	P19429Q6FGX2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNI3	ENST00000344887.10 link	c.368C>T	p.Thr123Met	missense_variant	Exon 6 of 8	1	NM_000363.5	ENSP00000341838.5		P19429
ENSG00000267110	ENST00000587871.1 link	n.*470C>T		downstream_gene_variant		5		ENSP00000473050.1		M0R381

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249290

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135294

show subpopulations

Gnomad AFR exome

AF:

0.0000646

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:2

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 123 of the TNNI3 protein (p.Thr123Met). This variant is present in population databases (rs397516345, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and unexplained cardiac arrest (PMID: 27532257, 35352813, 37652022). ClinVar contains an entry for this variant (Variation ID: 43376). 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 tolerated. 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. -

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 123 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/249290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

not specified

Uncertain:1

Mar 06, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Thr123Met variant in TNNI3 has not been reported in the literature, but has been identified by our laboratory in 1 adult with HCM and in 1 child with severe RVH (LMM unpublished data). This variant has not been identified in large and b road European American and African American populations by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS), though it may be common in oth er populations. Threonine (Thr) at position 123 is conserved in most mammals (ex cept squirrel and shrew), but not in more distantly related species, suggesting that a change at this position may be tolerated. Alternatively, this variant was predicted to be pathogenic using a computational tool clinically validated by o ur laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, additional studies are needed to fully as sess its clinical significance. -

TNNI3-related disorder

Uncertain:1

Feb 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TNNI3 c.368C>T variant is predicted to result in the amino acid substitution p.Thr123Met. This variant was reported as a variant of uncertain significance in an individual with hypertrophic cardiomyopathy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiomyopathy

Uncertain:1

Jun 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 123 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 30847666). This variant has been identified in 2/249290 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Cardiovascular phenotype

Uncertain:1

Mar 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368C>T (p.T123M) alteration is located in exon 6 (coding exon 6) of the TNNI3 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the threonine (T) at amino acid position 123 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

CardioboostCm

Benign

0.0049

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

D;D

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

0.0064

MutationAssessor

Benign

0.97

L;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.71

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.047

D;.

Sift4G

Benign

0.16

T;T

Polyphen

0.99

D;.

Vest4

0.38

MutPred

0.34

Gain of catalytic residue at T123 (P = 0.0375);.;

MVP

0.90

MPC

0.70

ClinPred

0.19

GERP RS

3.4

Varity_R

0.10

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