NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 5, 2024
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:: RCV000159290.13

Allele description [Variation Report for NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)]

NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)

Gene:

TNNT2:troponin T2, cardiac type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)

Other names:

p.R130C:CGT>TGT

HGVS:

NC_000001.11:g.201364369G>A
NG_007556.1:g.18309C>T
NM_000364.4:c.418C>T
NM_001001430.3:c.388C>T
NM_001001431.3:c.388C>T
NM_001001432.3:c.373C>T
NM_001276345.2:c.418C>TMANE SELECT
NM_001276346.2:c.298C>T
NM_001276347.2:c.388C>T
NP_000355.2:p.Arg140Cys
NP_001001430.1:p.Arg130Cys
NP_001001431.1:p.Arg130Cys
NP_001001432.1:p.Arg125Cys
NP_001263274.1:p.Arg140Cys
NP_001263275.1:p.Arg100Cys
NP_001263276.1:p.Arg130Cys
LRG_431t1:c.418C>T
LRG_431:g.18309C>T
LRG_431p1:p.Arg140Cys
NC_000001.10:g.201333497G>A
NM_000364.3:c.418C>T
NM_001001430.1:c.388C>T
NM_001001430.2:c.388C>T
NM_001001430.3:c.388C>T
c.388C>T

Protein change:

R100C

Links:

dbSNP: rs397516463

NCBI 1000 Genomes Browser:

rs397516463

Molecular consequence:

NM_000364.4:c.418C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.373C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.418C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276346.2:c.298C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209236	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 5, 2024)	germline	clinical testing	Citation Link,
SCV000280524	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (May 1, 2015)	germline	clinical testing
SCV002103193	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2021)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 8951566, 14636924, 15563892, 17456375, 18533079, 23283745, 23494605, 25524337, 26914223, 27532257, 30297972, 30555609, 14722098, 28973951, 32581830, 32690703, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000209236

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 5, 2024)

germline

clinical testing

Citation Link,

SCV000280524

Stanford Center for Inherited Cardiovascular Disease, Stanford University

no assertion criteria provided

Likely pathogenic
(May 1, 2015)

germline

clinical testing

SCV002103193

Mayo Clinic Laboratories, Mayo Clinic

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 20, 2021)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical manifestations of hypertrophic cardiomyopathy with mutations in the cardiac beta-myosin heavy chain gene or cardiac troponin T gene.

Koga Y, Toshima H, Kimura A, Harada H, Koyanagi T, Nishi H, Nakata M, Imaizumi T.

J Card Fail. 1996 Dec;2(4 Suppl):S97-103.

PubMed [citation]

PMID:: 8951566

Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in tuscany.

Torricelli F, Girolami F, Olivotto I, Passerini I, Frusconi S, Vargiu D, Richard P, Cecchi F.

Am J Cardiol. 2003 Dec 1;92(11):1358-62.

PubMed [citation]

PMID:: 14636924

See all PubMed Citations (17)

Details of each submission

From GeneDx, SCV000209236.16

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

Description

Published functional studies demonstrate a damaging effect with this variant altering the contractile properties of cardiac fibers (PMID: 14722098); Not observed at significant frequency 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: 23283745, 24474197, 28420666, 23074333, 25524337, 26914223, 27532257, 28973951, 17456375, 15563892, 14636924, 30393638, 18533079, 21310275, 8951566, 30555609, 32690703, 32581830, 33025817, 23494605, 28193612, 34929444, 14722098)

#	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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280524.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 variant Arg130Cys (R130C; C>T at the nucleotide level) This variant has been reported in at least 5 unrelated cases of HCM, with segregation data for at least 3 families. Koga et al. (1996) first detected it in 3 different Japanese families. The variant was “present in all affected family members” (a total of 6 people), but specific segregation data is not provided. Toricelli et al. (2003) reported Arg130Cys in an HCM patient from Tuscany with only weak segregation data: The variant was found in the proband and his affected sister. Olivotto et al. (2008) appear to be referring to that same proband. Song et al. (2005) found the variant in one Chinese family with a history of SCD, where it segregated with disease in 4 affected family members—although their degree of relationship is not reported. (Also supposedly mentioned in an abstract by Nakata et al. in 1996.) Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. This includes Lys124Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database), Arg131Trp (in DCM/LVNC; Mogensen et al. 2004), Arg131Gly (in DCM; Willott et al. 2010), Arg134Gly (in DCM; Hershberger et al. 2009; Willott et al. 2010), and Arg139His (Morales et al. 2010). This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Cysteine (capable of forming disulfide bridges). The Arginine at codon 130 is completely conserved across 32 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In vitro data from Harada & Potter (2004) shows the variant to alter the contractile properties of skinned cardiac fibers. In total the variant has not been seen in ~5670 published controls and publicly available population datasets. There is no variation at codon 130 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Koga et al. (1996) did not detect Arg130Cys in more than 100 Japanese controls. Toricelli et al. (2003) did not find it in 150 healthy controls from Tuscany. Song et al. (2005) did not find it in 120 Chinese 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		5	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV002103193.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

PS3, PP1_strong, PS4_moderate, PM2_supporting, PM3_supporting, PP3

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

Last Updated: Sep 29, 2024

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