NM_006757.4(TNNT3):c.187C>T (p.Arg63Cys) AND Arthrogryposis, distal, type 2B2

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Oct 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000787280.7

Allele description [Variation Report for NM_006757.4(TNNT3):c.187C>T (p.Arg63Cys)]

NM_006757.4(TNNT3):c.187C>T (p.Arg63Cys)

Gene:

TNNT3:troponin T3, fast skeletal type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.5

Genomic location:

Preferred name:

NM_006757.4(TNNT3):c.187C>T (p.Arg63Cys)

Other names:

p.Arg63Cys

HGVS:

NC_000011.10:g.1933736C>T
NM_001042780.3:c.163C>T
NM_001042781.3:c.181C>T
NM_001042782.3:c.163C>T
NM_001297646.2:c.163C>T
NM_001363561.2:c.196C>T
NM_001367842.1:c.181C>T
NM_001367843.1:c.181C>T
NM_001367844.1:c.163C>T
NM_001367845.1:c.163C>T
NM_001367846.1:c.220C>T
NM_001367847.1:c.196C>T
NM_001367848.1:c.184C>T
NM_001367849.1:c.175C>T
NM_001367850.1:c.130C>T
NM_001367851.1:c.-18C>T
NM_001367852.1:c.-18C>T
NM_006757.4:c.187C>TMANE SELECT
NP_001036245.1:p.Arg55Cys
NP_001036246.1:p.Arg61Cys
NP_001036247.1:p.Arg55Cys
NP_001284575.1:p.Arg55Cys
NP_001350490.1:p.Arg66Cys
NP_001354771.1:p.Arg61Cys
NP_001354772.1:p.Arg61Cys
NP_001354773.1:p.Arg55Cys
NP_001354774.1:p.Arg55Cys
NP_001354775.1:p.Arg74Cys
NP_001354776.1:p.Arg66Cys
NP_001354777.1:p.Arg62Cys
NP_001354778.1:p.Arg59Cys
NP_001354779.1:p.Arg44Cys
NP_006748.1:p.Arg63Cys
LRG_850t1:c.187C>T
LRG_850p1:p.Arg63Cys
NC_000011.9:g.1954966C>T
NM_001042782.2:c.163C>T
NM_006757.3:c.187C>T
NM_006757.4:c.187C>T
p.(Arg63Cys)

Protein change:

R44C; ARG63CYS

Links:

Leiden Muscular Dystrophy (TNNT3): TNNT3_00010; OMIM: 600692.0002; dbSNP: rs199474721

NCBI 1000 Genomes Browser:

rs199474721

Molecular consequence:

NM_001367851.1:c.-18C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001367852.1:c.-18C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001042780.3:c.163C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042781.3:c.181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042782.3:c.163C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001297646.2:c.163C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363561.2:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367842.1:c.181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367843.1:c.181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367844.1:c.163C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367845.1:c.163C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367846.1:c.220C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367847.1:c.196C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367848.1:c.184C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367849.1:c.175C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001367850.1:c.130C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006757.4:c.187C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

Observations:

Condition(s)

Name:: Arthrogryposis, distal, type 2B2
Identifiers:: MONDO: MONDO:0032750; MedGen: C5193097; OMIM: 618435

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914181	OMIM	no assertion criteria provided	Pathogenic (May 1, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000926212	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	no assertion criteria provided	Pathogenic (May 3, 2019)	de novo	clinical testing
SCV000996474	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 22, 2019)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 21402185, 25741868
SCV001167516	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	no assertion criteria provided	Uncertain significance	unknown	research
SCV002817385	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005382212	Institute of Immunology and Genetics Kaiserslautern	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	1	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus.

Zhao N, Jiang M, Han W, Bian C, Li X, Huang F, Kong Q, Li J.

Eur J Med Genet. 2011 May-Jun;54(3):351-3. doi: 10.1016/j.ejmg.2011.03.002. Epub 2011 Mar 12.

PubMed [citation]

PMID:: 21402185

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000914181.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In all 5 affected members of a Chinese family segregating (DA2B2; 618435) mapped to chromosome 11p15, Zhao et al. (2011) identified heterozygosity for a missense mutation (R63C; 600692.0002) in the TNNT3 gene. The mutation, which occurred at the same codon previously reported in patients with DA2B2 (600692.0001), was not found in an unaffected member of the family or in 100 controls.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, SCV000926212.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV000996474.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV001167516.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	1	not provided

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV002817385.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Immunology and Genetics Kaiserslautern, SCV005382212.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG Criteria: PM2, PM5, PP3, PP5; Variant was found in heterozygous state.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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