NM_001276345.2(TNNT2):c.460C>T (p.Arg154Trp) AND Cardiomyopathy

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 3, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000777699.3

Allele description [Variation Report for NM_001276345.2(TNNT2):c.460C>T (p.Arg154Trp)]

NM_001276345.2(TNNT2):c.460C>T (p.Arg154Trp)

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.460C>T (p.Arg154Trp)
Other names:
R144W(missense/non-synonymousmutation)
HGVS:
  • NC_000001.11:g.201364327G>A
  • NG_007556.1:g.18351C>T
  • NM_000364.4:c.460C>T
  • NM_001001430.3:c.430C>T
  • NM_001001431.3:c.430C>T
  • NM_001001432.3:c.415C>T
  • NM_001276345.2:c.460C>TMANE SELECT
  • NM_001276346.2:c.340C>T
  • NM_001276347.2:c.430C>T
  • NP_000355.2:p.Arg154Trp
  • NP_001001430.1:p.Arg144Trp
  • NP_001001431.1:p.Arg144Trp
  • NP_001001432.1:p.Arg139Trp
  • NP_001263274.1:p.Arg154Trp
  • NP_001263275.1:p.Arg114Trp
  • NP_001263276.1:p.Arg144Trp
  • LRG_431t1:c.460C>T
  • LRG_431:g.18351C>T
  • LRG_431p1:p.Arg154Trp
  • NC_000001.10:g.201333455G>A
  • NM_001001430.1:c.430C>T
  • NM_001001430.2:c.430C>T
Protein change:
R114W
Links:
dbSNP: rs483352832
NCBI 1000 Genomes Browser:
rs483352832
Molecular consequence:
  • NM_000364.4:c.460C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001430.3:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001431.3:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001432.3:c.415C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276345.2:c.460C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276346.2:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276347.2:c.430C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiomyopathy (CMYO)
Identifiers:
MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000913632Color Health, Inccriteria provided, single submitter
Uncertain significance
(Feb 3, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001333852CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontariocriteria provided, single submitter
Likely pathogenic
(Aug 20, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Description

This missense variant replaces arginine with tryptophan at codon 144 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of this observation is not known. This variant has been shown to segregate with dilated cardiomyopathy in an Indian family (4 affected carriers and 8 unaffected non-carriers) (PMID: 24992688). This variant has also been identified in 8/249866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

SCV000913632

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Color Health, Inc, SCV000913632.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario, SCV001333852.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 13, 2021

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