NM_000364.3(TNNT2):c.421C>T (p.Arg141Trp) AND Left ventricular noncompaction 6

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1) (Last evaluated: Sep 30, 2013)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000364.3(TNNT2):c.421C>T (p.Arg141Trp)]

NM_000364.3(TNNT2):c.421C>T (p.Arg141Trp)

TNNT2:troponin T type 2 (cardiac) [Gene - OMIM]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000364.3(TNNT2):c.421C>T (p.Arg141Trp)
  • 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
  • p.R131W:CGG>TGG
Protein change:
R126W; ARG131TRP
OMIM: 191045.0008; dbSNP: 74315380
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000364.3:c.421C>T - missense variant - [Sequence Ontology: SO:0001583]


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

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Assertion and evidence details

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

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

SCV000060239Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
(LMM Criteria)
Likely pathogenic
(Sep 30, 2013)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided22not providednot providednot providedliterature only, clinical testing



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]

Mutations in sarcomere protein genes in left ventricular noncompaction.

Klaassen S, Probst S, Oechslin E, Gerull B, Krings G, Schuler P, Greutmann M, Hürlimann D, Yegitbasi M, Pons L, Gramlich M, Drenckhahn JD, Heuser A, Berger F, Jenni R, Thierfelder L.

Circulation. 2008 Jun 3;117(22):2893-901. doi: 10.1161/CIRCULATIONAHA.107.746164. Epub 2008 May 27.

PubMed [citation]
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000033473.1

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


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.

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

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000060239.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (7)


The Arg131Trp variant in TNNT2 has been identified in 1 individual with LVNC where it was reported to have occurred de novo (Klaassen 2008) and has now been identified by our laboratory in 2 individuals with DCM. It was not identified in large population studies. Additionally, studies have shown that the Arg131Trp variant alters calcium binding properties of the thin filaments (Robinson 2007, Lui 2012). However, these in vitro assays may not accurately represent biological function. Arginine (Arg) at position 131 is highly conserved in mammals and across evolutionarily distant species and the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

Last Updated: Oct 11, 2015