NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 22, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000619398.4

Allele description [Variation Report for NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)]

NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)

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.311G>T (p.Arg104Leu)

Other names:

p.R94L:CGC>CTC

HGVS:

NC_000001.11:g.201365291C>A
NG_007556.1:g.17387G>T
NM_000364.4:c.311G>T
NM_001001430.3:c.281G>T
NM_001001431.3:c.281G>T
NM_001001432.3:c.266G>T
NM_001276345.2:c.311G>TMANE SELECT
NM_001276346.2:c.291+319G>T
NM_001276347.2:c.281G>T
NP_000355.2:p.Arg104Leu
NP_001001430.1:p.Arg94Leu
NP_001001431.1:p.Arg94Leu
NP_001001432.1:p.Arg89Leu
NP_001263274.1:p.Arg104Leu
NP_001263276.1:p.Arg94Leu
LRG_431t1:c.311G>T
LRG_431:g.17387G>T
LRG_431p1:p.Arg104Leu
NC_000001.10:g.201334419C>A
NM_001001430.1:c.281G>T
NM_001001430.2:c.281G>T
NM_001276346.1:c.291+319G>T
c.281G>T

Protein change:

R104L

Links:

dbSNP: rs397516457

NCBI 1000 Genomes Browser:

rs397516457

Molecular consequence:

NM_001276346.2:c.291+319G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000364.4:c.311G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001001430.3:c.281G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001001431.3:c.281G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001001432.3:c.266G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276345.2:c.311G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276347.2:c.281G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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BGS1 [Zymoseptoria tritici IPO323]
BGS1 [Zymoseptoria tritici IPO323]
Gene ID:13396235

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740033	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 22, 2024)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 10525521, 10978365, 11560853, 11606294, 14654368, 14722098, 18258667, 20513729, 20624503, 22144547, 23074333, 25611685, 27532257 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740033

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 22, 2024)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy.

Varnava A, Baboonian C, Davison F, de Cruz L, Elliott PM, Davies MJ, McKenna WJ.

Heart. 1999 Nov;82(5):621-4.

PubMed [citation]

PMID:: 10525521
PMCID:: PMC1760789

Cytosine methylation confers instability on the cardiac troponin T gene in hypertrophic cardiomyopathy.

D'Cruz LG, Baboonian C, Phillimore HE, Taylor R, Elliott PM, Varnava A, Davison F, McKenna WJ, Carter ND.

J Med Genet. 2000 Sep;37(9):E18. No abstract available.

PubMed [citation]

PMID:: 10978365
PMCID:: PMC1734704

See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV000740033.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The p.R94L pathogenic mutation (also known as c.281G>T), located in coding exon 8 of the TNNT2 gene, results from a G to T substitution at nucleotide position 281. The arginine at codon 94 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in several hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with disease in a family (Varnava A et al. Heart. 1999;82:621-4; Melacini P et al. Eur Heart J. 2010 Sep;31(17):2111-23; Pasquale F et al. Circ Cardiovasc Genet. 2012 Feb;5(1):10-7). Functional in vitro analyses involving skinned cardiac fibers have suggested that this alteration affects TNNT2 protein function (Lu QW et al. J Mol Cell Cardiol. 2003;35:1421-7). In addition, an alteration involving the same amino acid, p.R94H (c.281G>A), has been reported in individuals with HCM (Millat G et al. Eur J Med Genet. 2010;53:261-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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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