chr11-1933737-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_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 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

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

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 Lovd as [Pathogenic].
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 rank MANE Protein UniProt
TNNT3NM_006757.4 linkc.188G>A p.Arg63His missense_variant Exon 10 of 16 ENST00000278317.11 NP_006748.1 P45378-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNNT3ENST00000278317.11 linkc.188G>A p.Arg63His missense_variant Exon 10 of 16 5 NM_006757.4 ENSP00000278317.6 P45378-2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152222
Hom.:
0
Cov.:
33
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:
1
AN:
1460688
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
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:
0
AN:
152222
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
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:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arthrogryposis, distal, type 2B2 Pathogenic:7
Aug 22, 2019
SIB Swiss Institute of Bioinformatics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

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. -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM2_Supporting+PS4_Moderate+PM6+PP1_Strong+PP4+PM5+PP3_Strong -

Aug 23, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 23, 2022
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 -

May 01, 2009
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Institute of Human Genetics, University Hospital of Duesseldorf
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 14, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:6Other:1
Mar 18, 2012
Leiden Muscular Dystrophy (TNNT3)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Aug 10, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 30, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM5, PP4, PS4, PM2_SUP, PP1 -

May 01, 2018
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 28, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Arthyrgryposis, distal, type 2B Pathogenic:1
Mar 05, 2015
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.90
.;D;.;.;.;.;.;.;.;.;D;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.94
D;D;D;.;D;D;D;.;D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
.;.;.;.;.;.;.;.;.;.;M;.;.
PrimateAI
Uncertain
0.78
T
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
D
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.

Other links and lift over

dbSNP: rs121434638; hg19: chr11-1954967; COSMIC: COSV53486643; COSMIC: COSV53486643; API