rs121434638

Positions:

chr11-1933737-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_006757.4(TNNT3):c.188G>A(p.Arg63His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNNT3
NM_006757.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 7.58

Variant links:

Genes affected

TNNT3 (HGNC:11950): (troponin T3, fast skeletal type) The binding of Ca(2+) to the trimeric troponin complex initiates the process of muscle contraction. Increased Ca(2+) concentrations produce a conformational change in the troponin complex that is transmitted to tropomyosin dimers situated along actin filaments. The altered conformation permits increased interaction between a myosin head and an actin filament which, ultimately, produces a muscle contraction. The troponin complex has protein subunits C, I, and T. Subunit C binds Ca(2+) and subunit I binds to actin and inhibits actin-myosin interaction. Subunit T binds the troponin complex to the tropomyosin complex and is also required for Ca(2+)-mediated activation of actomyosin ATPase activity. There are 3 different troponin T genes that encode tissue-specific isoforms of subunit T for fast skeletal-, slow skeletal-, and cardiac-muscle. This gene encodes fast skeletal troponin T protein; also known as troponin T type 3. Alternative splicing results in multiple transcript variants encoding additional distinct troponin T type 3 isoforms. A developmentally regulated switch between fetal/neonatal and adult troponin T type 3 isoforms occurs. Additional splice variants have been described but their biological validity has not been established. Mutations in this gene may cause distal arthrogryposis multiplex congenita type 2B (DA2B). [provided by RefSeq, Oct 2009]

TNNT3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a compositionally_biased_region Basic and acidic residues (size 26) in uniprot entity TNNT3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_006757.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-1933736-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 11-1933737-G-A is Pathogenic according to our data. Variant chr11-1933737-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-1933737-G-A is described in UniProt as null. Variant chr11-1933737-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNNT3	NM_006757.4 linkuse as main transcript	c.188G>A	p.Arg63His	missense_variant	10/16	ENST00000278317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNNT3	ENST00000278317.11 linkuse as main transcript	c.188G>A	p.Arg63His	missense_variant	10/16	5	NM_006757.4	A2	P45378-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152222

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726618

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

Gnomad4 AFR

AF:

0.00

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2021	Not observed 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: 19142688, 23401156, 24319099, 12865991, 25337069, 30216196, 31974414, 32779773, 26915936) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT3)	Mar 18, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 30, 2021	PP3, PM5, PP4, PS4, PM2_SUP, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 10, 2023	- -

Arthrogryposis, distal, type 2B2

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2023	Variant summary: TNNT3 c.188G>A (p.Arg63His) results in a non-conservative amino acid change in the encoded protein sequence, altering a highly conserved residue (HGMD) in which two other missense variants (p.Arg63Cys, p.Arg63Ser) have been classified as pathogenic or likely pathogenic by ClinVar submitters. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249900 control chromosomes (gnomAD). c.188G>A has been reported in the literature in multiple individuals affected with distal arthrogryposis type 1 and 2b (Sung_2003, Gurnett_2009, Laquerriere_2014, Vora_2020). The variant was reported as a de novo occurrence in some of these cases, as well as in an internal case with features suggestive of possible arthrogryposis. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19142688, 12865991, 24319099, 31974414). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Dec 23, 2022	The de novo heterozygous c.188G>A, p.(Arg63His) variant identified in the TNNT3 gene substitutes a well conserved Arginine for Histidine at amino acid 63/259 (exon 10/16). This variant is absent from population databases (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be damaging to the canonical transcript (REVEL; score=0.959). This variant is reported as Pathogenic in ClinVar (VarID:8913, 9 submissions, no conflicts), and a different amino acid change at the same amino acid, p.Arg63Cys is also classified as Pathogenic (VarID:31874). The c.188G>A, p.(Arg63His) variant identified in this fetus has been reported in many affected individuals in the literature [PMID:25337069, 32779773, 31974414, 23401156, 12865991] and functional studies suggest that the p.Arg63His variant significantly enhances ATPase activity and increases calcium sensitivity [PMID:17194691]. Given its absence in population databases, observation in many affected individuals, functional studies, and presence de novo here, the heterozygous c.188G>A, p.(Arg63His) variant identified in the TNNT3 gene is reported as Pathogenic -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Aug 22, 2019	This variant is interpreted as a Pathogenic for Arthrogryposis, distal, 2B2, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PM6, PP3, PP1-Strong, PS4-Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 14, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -

Arthyrgryposis, distal, type 2B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

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

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

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

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.85

MutPred

0.85

Loss of MoRF binding (P = 0.088);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

3.7

Varity_R

0.79

gMVP

0.88

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