NM_001001430.2(TNNT2):c.391C>T (p.Arg131Trp) AND Left ventricular noncompaction 6

Clinical significance:Pathogenic (Last evaluated: Nov 28, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000013226.27

Allele description [Variation Report for NM_001001430.2(TNNT2):c.391C>T (p.Arg131Trp)]

NM_001001430.2(TNNT2):c.391C>T (p.Arg131Trp)

Gene:
TNNT2:troponin T2, cardiac type [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q32.1
Genomic location:
Preferred name:
NM_001001430.2(TNNT2):c.391C>T (p.Arg131Trp)
Other names:
p.R131W:CGG>TGG
HGVS:
  • NC_000001.11:g.201364366G>A
  • NG_007556.1:g.18312C>T
  • NM_000364.3:c.421C>T
  • NM_001001430.2:c.391C>T
  • NM_001001432.2:c.376C>T
  • NP_000355.2:p.Arg141Trp
  • NP_001001430.1:p.Arg131Trp
  • NP_001001432.1:p.Arg126Trp
  • NC_000001.10:g.201333494G>A
  • NM_000364.2:c.421C>T
  • NM_001001430.1:c.391C>T
  • NM_001001432.1:c.376C>T
  • c.391C>T
Protein change:
R126W; ARG131TRP
Links:
OMIM: 191045.0008; dbSNP: 74315380
NCBI 1000 Genomes Browser:
rs74315380
Allele Frequency:
NaN
Molecular consequence:
  • NM_000364.3:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Left ventricular noncompaction 6 (CMD1D)
Synonyms:
Dilated cardiomyopathy 1D
Identifiers:
MedGen: C1832243; Orphanet: 154; Orphanet: 54260; OMIM: 601494
Age of onset:
All ages
Prevalence:
1-9 / 100 000 154

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000033473OMIMno assertion criteria providedPathogenic
(Jun 3, 2008)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000541919Invitaecriteria provided, single submitter
Pathogenic
(Nov 28, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy.

Mogensen J, Murphy RT, Shaw T, Bahl A, Redwood C, Watkins H, Burke M, Elliott PM, McKenna WJ.

J Am Coll Cardiol. 2004 Nov 16;44(10):2033-40.

PubMed [citation]
PMID:
15542288

Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype.

Mirza M, Marston S, Willott R, Ashley C, Mogensen J, McKenna W, Robinson P, Redwood C, Watkins H.

J Biol Chem. 2005 Aug 5;280(31):28498-506. Epub 2005 May 27.

PubMed [citation]
PMID:
15923195
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000033473.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In a 28-year-old woman with dilated cardiomyopathy (601494), Mogensen et al. (2004) identified heterozygosity for an arg131-to-trp (R131W) substitution at a conserved residue in exon 10 of the TNNT2 gene. An older brother had died suddenly at 16 years of age; their mother had CMD and died of heart failure at 34 years of age. The mutation was not found in her unaffected older brother or father, or in 200 ethnically matched control chromosomes. Functional studies showed significant impairment of mutated troponin interaction compared with wildtype control, indicating an altered regulation of myocardial contractility.

Mirza et al. (2005) studied the R131W mutation and found that thin filaments reconstituted with a 1:1 ratio of mutant:wildtype proteins showed reduced Ca(2+) sensitivity of activation in ATPase and motility assays and a lower maximum Ca(2+) activation.

In a 20-year-old woman who presented in cardiogenic shock and was diagnosed with isolated left ventricular noncompaction (LVNC6; see 601494), Klaassen et al. (2008) identified heterozygosity for the R131W mutation in TNNT2. The patient had primarily midlateral and midinferior LVNC, left ventricular dilation, and impaired left ventricular systolic function. The de novo mutation was not present in her unaffected parents, and was not found in 360 control chromosomes.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000541919.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This sequence change replaces arginine with tryptophan at codon 131 of the TNNT2 protein (p.Arg131Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs74315380, ExAC 0.002%). This variant has been reported in the literature co-segregating with disease in one family affected with dilated cardiomyopathy (DCM) and left ventricular non compaction (LVNC) (PMID: 15542288). It has been shown to arise de novo in one individual affected with LVNC (PMID: 18506004). It has also been reported in unrelated individuals affected with DCM and LVNC (PMID: 21551322, 24119082). ClinVar contains an entry for this variant (Variation ID: 12415). Experimental studies have shown that this variant disrupts normal troponin function in in vitro motility assays (PMID: 15542288, 17932326, 22675533, 15923195). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 17, 2017