NM_003283.6:c.566G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_003283.6(TNNT1):c.566G>A(p.Arg189His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,519,274 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

TNNT1
NM_003283.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.22

Publications

4 publications found

Variant links:

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNNT1 Gene-Disease associations (from GenCC):

nemaline myopathy 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
nemaline myopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
nemaline myopathy 5C, autosomal dominant
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

TNNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT1	NM_003283.6 link	c.566G>A	p.Arg189His	missense_variant	Exon 11 of 14	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6 link	c.566G>A	p.Arg189His	missense_variant	Exon 11 of 14	1	NM_003283.6	ENSP00000467176.1

Frequencies

GnomAD3 genomes

AF:

0.0000470

AC:

AN:

148954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000104

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251160

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1370320

Hom.:

Cov.:

AF XY:

0.0000485

AC XY:

AN XY:

680618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30776

American (AMR)

AF:

0.0000240

AC:

AN:

41744

Ashkenazi Jewish (ASJ)

AF:

0.000483

AC:

AN:

22784

East Asian (EAS)

AF:

0.00

AC:

AN:

32756

South Asian (SAS)

AF:

0.00

AC:

AN:

85402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5278

European-Non Finnish (NFE)

AF:

0.0000446

AC:

AN:

1053166

Other (OTH)

AF:

0.0000555

AC:

AN:

54092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000470

AC:

AN:

148954

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40622

American (AMR)

AF:

0.00

AC:

AN:

14918

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00

AC:

AN:

4776

South Asian (SAS)

AF:

0.00

AC:

AN:

4486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

67296

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Mar 17, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNNT1: PM2, PP3 -

Inborn genetic diseases

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.566G>A (p.R189H) alteration is located in exon 11 (coding exon 10) of the TNNT1 gene. This alteration results from a G to A substitution at nucleotide position 566, causing the arginine (R) at amino acid position 189 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nemaline myopathy 5

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 189 of the TNNT1 protein (p.Arg189His). This variant is present in population databases (rs770079408, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TNNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 534401). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TNNT1 protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

.;.;.;D;D;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

.;D;D;D;D;D;.;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

.;.;M;.;M;.;.;.;.

PhyloP100

7.2

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.5

.;D;D;.;.;.;.;.;.

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

.;D;D;.;.;.;.;.;.

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;.

Polyphen

1.0

D;D;D;.;D;.;.;.;.

Vest4

0.85

MutPred

0.84

.;.;Loss of MoRF binding (P = 0.0396);.;Loss of MoRF binding (P = 0.0396);.;.;.;Loss of MoRF binding (P = 0.0396);

MVP

0.98

MPC

1.7

ClinPred

0.99

GERP RS

4.0

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.69

gMVP

0.66

Mutation Taster

=21/79

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over