NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln) AND not provided

Clinical significance:Pathogenic (Last evaluated: Apr 27, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000159281.8

Allele description [Variation Report for NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)]

NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)

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.305G>A (p.Arg102Gln)
Other names:
p.R92Q:CGG>CAG
HGVS:
  • NC_000001.11:g.201365297C>T
  • NG_007556.1:g.17381G>A
  • NM_000364.4:c.305G>A
  • NM_001001430.3:c.275G>A
  • NM_001001431.3:c.275G>A
  • NM_001001432.3:c.260G>A
  • NM_001276345.2:c.305G>AMANE SELECT
  • NM_001276346.2:c.291+313G>A
  • NM_001276347.2:c.275G>A
  • NP_000355.2:p.Arg102Gln
  • NP_001001430.1:p.Arg92Gln
  • NP_001001431.1:p.Arg92Gln
  • NP_001001432.1:p.Arg87Gln
  • NP_001263274.1:p.Arg102Gln
  • NP_001263276.1:p.Arg92Gln
  • LRG_431t1:c.305G>A
  • LRG_431:g.17381G>A
  • LRG_431p1:p.Arg102Gln
  • NC_000001.10:g.201334425C>T
  • NM_001001430.1:c.275G>A
  • NM_001001430.2:c.275G>A
  • c.275G>A
Protein change:
R102Q; ARG92GLN
Links:
OMIM: 191045.0002; dbSNP: rs121964856
NCBI 1000 Genomes Browser:
rs121964856
Molecular consequence:
  • NM_001276346.2:c.291+313G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000364.4:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001430.3:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001431.3:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001001432.3:c.260G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276345.2:c.305G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276347.2:c.275G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
9

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000209227GeneDxcriteria provided, single submitter
Pathogenic
(Apr 27, 2018)
germlineclinical testing

Citation Link,

SCV000280516Stanford Center for Inherited Cardiovascular Disease, Stanford Universityno assertion criteria providedPathogenic
(Jan 16, 2012)
germlineclinical testing

SCV001917971Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedPathogenicgermlineclinical testing

SCV001953929Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedPathogenicgermlineclinical testing

SCV002022367PerkinElmer Genomicsno assertion criteria providedPathogenic
(Jul 2, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided9not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000209227.11

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

Description

The R92Q variant in the TNNT2 gene has been published multiple times in association with HCM (Theirfelder L et al., 1994; Yanaga F et al., 1999; Palm T et al, 2001; Javadpour M et al., 2003; Torricelli F et al., 2003; Morita H et al., 2008; Liu et al., 2012; Tian et al., 2014; Ripoll-Vera et al., 2016) and has been identified in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. Thierfelder et al. (1994) initially reported that the R92Q variant co-segregated with HCM in six affected members from one family. Morita et al. (2008) also identified R92Q as de novo in a child with HCM. Multiple functional studies have demonstrated that R92Q impairs tropomyosin binding, and the myofibrillar assembly (Yanaga F et al., 1999; Palm T et al., 2001; Javadpour M et al., 2003; Liu et al., 2012). A pathogenic variant affecting the same residue (R92W) and pathogenic and likely pathogenic variants affecting nearby residues (R94C, R94H, R94L, K97N) have been reported in association with HCM in the Human Genome Mutation Database (Stenson P et al., 2014) and at GeneDx. Furthermore, R92Q is reported as a pathogenic or likely pathogenic variant by four other laboratories in ClinVar (SCV000060229.5, SCV000285648.3, SCV000299242.1, SCV000735554.1; Landrum et al., 2016). Lastly, the R92Q variant is not observed in large population cohorts (Lek et al., 2016).

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

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280516.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not 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. Based on the strong case data, strong segregation data, and mouse models, we consider it very likely disease causing. The variant has been seen in at least 8 unrelated cases of HCM (not including the patient) with good segregation data in one family and extensive functional data available—including in transgenic mouse models. In our own center we have seen this variant in at least three unrelated individuals with familial cardiomyopathy. Thierfelder et al. (1994) identified Arg92Gln in one HCM family; it segregated with disease in all 6 affected members (degree of relationship not reported; LOD score 4.1). Watkins et al. (1995) identified Arg92Gln in 3 unrelated HCM families. (LOD score 8.3.) Torricelli et al. (2003) identified it in an HCM case from Tuscany. Morita et al. (2008) found it had occurred de novo in a patient with HCM. Paternity was confirmed, and the parents were clinically unaffected. Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Leu and p.Arg92Trp (we categorize both as very likely disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Glu83Lys, Val85Leu, Asp86Ala, Arg94Leu, Arg94Cys, and Lys97Asn (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). Oberst et al. (1998) showed transgenic mice carrying Arg92Gln to have increased cardiac myocyte disarray, increased interstitial collagen synthesis, and diastolic dysfunction. Tardiff et al. (1999) also showed the transgenic mouse hearts to have increased interstitial fibrosis, hypercontractility, and diastolic dysfunction. In vitro functional data from Palm et al. (2001) suggests that a change at codon 92—whether Arg92Trp, Arg92Gln or Arg92Leu—impairs binding of troponin T to tropomyosin, and makes the protein less effective at promoting the binding of tropomyosin to actin. Takahashi-Yanaga et al. (2001) showed the variant to impair the inhibitory effect of Troponin I on the sarcomere. Hinkle & Tobacman (2003) showed the variant to impair folding of the troponin T tail domain. Javadpour et al. (2003) found significant changes in cardiac energetics in transgenic mice carrying the variant. [[Note: Other papers to address the altered properties of myocytes containing this variant include Marian et al. 1997, Morimoto et al. 1998, Sweeney et al. 1998, Rust et al.1999, Yanaga et al. 1999, Szczesna et al. 2000, Chandra et al. 2001, Montgomery et al. 2001, Robinson et al. 2002, Solaro et al. 2002, Maass et al. 2004, and others. These are not reviewed here.]] Jimenez & Tardiff (2011) found Arg92Gln transgenic mice had an increased incidence of heart block and a greater frequency of premature ventricular contractions after isoproterenol injections. They also had abnormal autonomic regulation of heart rate. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a polar, neutral Glutamine. The Arginine at codon 92 is highly conserved across 39 vertebrate species examined (it is a Lysine in medaka) and surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” In total the variant has not been seen in ~7030 published controls and publicly available population datsets. There is no variation at codon 92 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian African American individuals (as of July 2nd, 2014). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of July 2nd, 2014). The variant was not observed in published controls: Thierfelder et al. (1994) did not find Arg92Gln in 100 controls. Watkins et al. (1995) did not observe it in more than 100 control individuals, ethnicity not specified. Torricelli et al. (2003) did not find it in 150 healthy controls from Tuscany. Morita et al. (2008) did not find it in 180 ethnicity-matched controls.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided9not providednot providednot provided

From Clinical Genetics,Academic Medical Center - VKGL Data-share Consensus, SCV001917971.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Human Genetics - Radboudumc,Radboudumc - VKGL Data-share Consensus, SCV001953929.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From PerkinElmer Genomics, SCV002022367.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 28, 2021

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