NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp) AND not provided

Clinical significance:Pathogenic (Last evaluated: Dec 12, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000223699.5

Allele description [Variation Report for NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)]

NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)

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.547C>T (p.Arg183Trp)
HGVS:
  • NC_000001.11:g.201363349G>A
  • NG_007556.1:g.19329C>T
  • NM_000364.4:c.547C>T
  • NM_001001430.3:c.517C>T
  • NM_001001431.3:c.517C>T
  • NM_001001432.3:c.502C>T
  • NM_001276345.2:c.547C>TMANE SELECT
  • NM_001276346.2:c.427C>T
  • NM_001276347.2:c.517C>T
  • NP_000355.2:p.Arg183Trp
  • NP_001001430.1:p.Arg173Trp
  • NP_001001431.1:p.Arg173Trp
  • NP_001001432.1:p.Arg168Trp
  • NP_001263274.1:p.Arg183Trp
  • NP_001263275.1:p.Arg143Trp
  • NP_001263276.1:p.Arg173Trp
  • LRG_431t1:c.547C>T
  • LRG_431:g.19329C>T
  • LRG_431p1:p.Arg183Trp
  • NC_000001.10:g.201332477G>A
  • NM_001001430.1:c.517C>T
  • NM_001001430.2:c.517C>T
  • NM_001276345.1:c.547C>T
Protein change:
R143W
Links:
dbSNP: rs727503512
NCBI 1000 Genomes Browser:
rs727503512
Molecular consequence:
  • NM_000364.4:c.547C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001430.3:c.517C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001431.3:c.517C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001432.3:c.502C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276345.2:c.547C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276346.2:c.427C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276347.2:c.517C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000280527Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedLikely pathogenic
(Aug 25, 2011)
germlineclinical testing

SCV000616898GeneDxcriteria provided, single submitter
Pathogenic
(Dec 12, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided3not providednot providednot providednot providedclinical testing

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280527.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot 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. p.Arg173Trp (c. 517C>T). At the time of testing this variant was novel (had not been reported in association with cardiomyopathy or as a benign common variant), however it has now been seen in a total of 3 unrelated individuals with cardiomyopathy. An unpublished study conducted in our laboratory demonstrated segregation of the variant in a total of four family members with a DCM diagnosis (Liu et al. 2012 published iPSC studies using this family's DNA). Since testing was completed 3 years ago we contacted the testing lab for an update on this variant and they shared that 1 additional individual (no relation to our proband) tested for DCM was genotype positive for the variant. In addition, Millat et al 2010 reported this variant in a patient with HCM (few clinical details and no segregation data were provided). This is a non conservative amino acid change with a hydrophilic, polar Arginine replaced with a hydrophobic, nonpolar Tryptophan. This variant has not been reported as a benign polymorphism (dbSNP, Google). A variant at the same codon, Arg173Gln, has been seen in at least 3 unrelated families with DCM and/or sudden death (including a SCICD family; please see that variant analysis) and shown to segregate with disease in 5 members of one published family with DCM. Variants in nearby codons (p.Ala172Ser and p.Ser179Phe) have been reported in association with cardiomyopathy (Stefanelli et al 2004 and Ho et al 2000). In silico analysis (PolyPhen) predicts the amino acid change to be damaging to protein structure/function. Arginine is highly conserved at residue 173 across species. This variant was not observed in 335 presumably healthy individuals of mixed ethnicity tested at the testing lab The variant is not listed in dbSNP or 1000 genomes.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not providednot providednot provided

From GeneDx, SCV000616898.2

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

Description

The R173W variant in the TNNT2 gene has been reported to segregate with DCM in a large five-generation pedigree, with 12 affected family members all harboring R173W (Campbell et al., 2013). Campbell et al. (2013) also reported R173W segregated with DCM in a second family in the study registry. The R173W variant is not observed in large population cohorts (Lek et al., 2016). The R173W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect, consistent with functional studies in cardiomyocytes generated from induced pluripotent stem cells from patients of a family harboring R173W, which exhibited altered Ca2+ handling and impaired myofilament regulation (Sun et al., 2012). Another variant in the same residue (R173Q) has been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. We interpret R173W as a pathogenic variant

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

Last Updated: May 10, 2021

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