11-1933736-C-T

Position:

• chr11-1933736-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006757.4(TNNT3):​c.187C>T​(p.Arg63Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNNT3 NM_006757.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1 O:1
• Conservation: PhyloP100: 1.45

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]

ACMG classification

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 chr11-1933737-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-1933736-C-T is Pathogenic according to our data. 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. Variant chr11-1933736-C-T is described in UniProt as null. Variant chr11-1933736-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNNT3	NM_006757.4	c.187C>T	p.Arg63Cys	missense_variant	10/16	ENST00000278317.11	NP_006748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNNT3	ENST00000278317.11	c.187C>T	p.Arg63Cys	missense_variant	10/16	5	NM_006757.4	ENSP00000278317	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arthrogryposis, distal, type 2B2 Pathogenic:5 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	May 03, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Oct 12, 2023	ACMG Criteria: PM2, PM5, PP3, PP5; Variant was found in heterozygous state. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 15, 2022	A heterozygous missense variation in exon 10 of the TNNT3 gene that results in the amino acid substitution of Cysteine for Arginine at codon 63 (p.Arg63Cys) was detected . The observed variation has previously been reported in patients affected with distal arthrogryposis [PMID:21402185]. This variant has not been reported in the 1000 genomes, gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Aug 22, 2019	This variant is interpreted as a Likely pathogenic for Arthrogryposis, distal, 2B2, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PP1, PM5. -
Uncertain significance, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2011	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (TNNT3)	Mar 18, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2021	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31230720, 23401156, 21402185, 26774798, 34766372, 33977145) -

Arthyrgryposis, distal, type 2B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;.;.;.;.;.;.;.;D;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D;.;D;D;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.93	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;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;D;D;.;.;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;.;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;.;D;D;D
Polyphen		1.0	D;.;.;D;D;.;.;D;D;D;.;.;.
Vest4		0.90
MutPred		0.82		Loss of MoRF binding (P = 0.0771);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.61
gMVP		0.92

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

Other links and lift over

dbSNP: rs199474721; hg19: chr11-1954966; COSMIC: COSV53486520; COSMIC: COSV53486520;