VCV000031874.17 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 31874 Accession: VCV000031874.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 1933736 (GRCh38) [ NCBI UCSC ] 11: 1954966 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 26, 2024	Oct 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006757.4:c.187C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006748.1:p.Arg63Cys	missense
NM_001042780.3:c.163C>T	NP_001036245.1:p.Arg55Cys	missense
NM_001042781.3:c.181C>T	NP_001036246.1:p.Arg61Cys	missense
NM_001042782.3:c.163C>T	NP_001036247.1:p.Arg55Cys	missense
NM_001297646.2:c.163C>T	NP_001284575.1:p.Arg55Cys	missense
NM_001363561.2:c.196C>T	NP_001350490.1:p.Arg66Cys	missense
NM_001367842.1:c.181C>T	NP_001354771.1:p.Arg61Cys	missense
NM_001367843.1:c.181C>T	NP_001354772.1:p.Arg61Cys	missense
NM_001367844.1:c.163C>T	NP_001354773.1:p.Arg55Cys	missense
NM_001367845.1:c.163C>T	NP_001354774.1:p.Arg55Cys	missense
NM_001367846.1:c.220C>T	NP_001354775.1:p.Arg74Cys	missense
NM_001367847.1:c.196C>T	NP_001354776.1:p.Arg66Cys	missense
NM_001367848.1:c.184C>T	NP_001354777.1:p.Arg62Cys	missense
NM_001367849.1:c.175C>T	NP_001354778.1:p.Arg59Cys	missense
NM_001367850.1:c.130C>T	NP_001354779.1:p.Arg44Cys	missense
NM_001367851.1:c.-18C>T		5 prime UTR
NM_001367852.1:c.-18C>T		5 prime UTR
NC_000011.10:g.1933736C>T
NC_000011.9:g.1954966C>T
LRG_850t1:c.187C>T	LRG_850p1:p.Arg63Cys

... more HGVS ... less HGVS

Protein change

R63C, R62C, R66C, R44C, R55C, R61C, R74C, R59C

Other names

p.Arg63Cys

Canonical SPDI

NC_000011.10:1933735:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

functional variant; Sequence Ontology [ SO:0001536]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA208350 Leiden Muscular Dystrophy (TNNT3): TNNT3_00010 OMIM: 600692.0002 dbSNP: rs199474721 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TNNT3		-	-	GRCh38 GRCh38 GRCh37	246	287

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, single submitter	Dec 10, 2021	RCV000024570.7
Arthyrgryposis, distal, type 2B	Pathogenic (1)	criteria provided, single submitter	Jul 1, 2015	RCV000194279.6
Arthrogryposis, distal, type 2B2	Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 12, 2023	RCV000787280.7

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 22, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Arthrogryposis, distal, type 2B2 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000996474.1 First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019	Publications: PubMed (1) PubMed: 21402185 Comment: 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.
Likely pathogenic (Dec 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthrogryposis, distal, type 2B2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV002817385.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Microcephaly (present) , Generalized hypotonia (present) , Long philtrum (present) , Atrial septal defect (present) , Inguinal hernia (present) , Premature birth (present) , Flexion … (more) Microcephaly (present) , Generalized hypotonia (present) , Long philtrum (present) , Atrial septal defect (present) , Inguinal hernia (present) , Premature birth (present) , Flexion contracture (present) , Small for gestational age (present) , Hypertelorism (present) , Growth delay (present) (less) Age: 0-9 years Sex: male Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (Dec 10, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001813516.3 First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jul 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthyrgryposis, distal, type 2B Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000249170.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Likely pathogenic (Oct 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arthrogryposis, distal, type 2B2 Affected status: yes Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382212.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PM2, PM5, PP3, PP5; Variant was found in heterozygous state. Clinical Features: Global developmental delay (present) , Microcephaly (present) , Flexion contracture of digit (present) , Short stature (present) , Pes planus (present)
Pathogenic (May 01, 2011)	no assertion criteria provided Method: literature only	ARTHROGRYPOSIS, DISTAL, TYPE 2B2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000914181.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019	Publications: PubMed (1) PubMed: 21402185 Comment on evidence: 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 … (more) 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. (less)
Pathogenic (May 03, 2019)	no assertion criteria provided Method: clinical testing	Arthrogryposis, distal, type 2B2 Affected status: yes Allele origin: de novo	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust Accession: SCV000926212.1 First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019
Uncertain significance (-)	no assertion criteria provided Method: research	Arthrogryposis, distal, type 2B2 This variant was identified in an (more...) (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV001167516.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Number of individuals with the variant: 1
not provided (Mar 18, 2012)	no classification provided Method: curation	not specified Affected status: not provided Allele origin: germline	Leiden Muscular Dystrophy (TNNT3) Accession: SCV000045874.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013

Comment:

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.

Comment:

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)

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
has functional consequence			Leiden Muscular Dystrophy (TNNT3) Accession: SCV000045874.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A novel mutation in TNNT3 associated with Sheldon-Hall syndrome in a Chinese family with vertical talus.	Zhao N	European journal of medical genetics	2011	PMID: 21402185

Text-mined citations for rs199474721 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199474721 ...