ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.305G>A (p.Arg102Gln) (rs121964856)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211865 SCV000060229 pathogenic Hypertrophic cardiomyopathy 2018-07-10 criteria provided, single submitter clinical testing The p.Arg92Gln variant in TNNT2 has been reported in >15 individuals with HCM, i ncluding one de novo occurrence, and segregated with disease in >15 affected rel atives (Thierfelder 1994, Watkins 1995, Morita 2008, Olivotto 2008, Strijack 200 8, Ripoll-Vera 2016, Walsh, 2017, LMM data). In addition, this was absent from l arge population studies. In vitro functional studies have shown that the Arg92Gl n variant impacts protein function (Marian 1997, Yanaga 1999, Robinson 2002, Liu 2012) and transgenic mice carrying this variant develop HCM (Chandar 2001, Ferr antini 2017). In summary, this variant meets criteria to be classified as pathog enic for HCM in an autosomal dominant manner based on case observations, segrega tion studies, absence from controls, and functional evidence. ACMG/AMP Criteria applied: PS3, PS4, PP1_Strong, PM2.
GeneDx RCV000159281 SCV000209227 pathogenic not provided 2018-04-27 criteria provided, single submitter clinical testing 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).
Invitae RCV000627784 SCV000285648 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 92 of the TNNT2 protein (p.Arg92Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypertrophic cardiomyopathy (HCM) in many families (PMID: 8205619, 7898523). In addition, it has been described in several individuals affected with HCM (PMID: 8951566, 23233322, 25524337), in one individual with left ventricular non-compaction (LVNC) (PMID: 24691700), in one individual with an atypical pattern of myocardial scarring (PMID: 19087273) and in one individual with inducible malignant ventricular tachyarrhythmia (PMID: 19487599). This variant has also been suggested to have arisen de novo in an individual affected with HCM (PMID: 18403758). ClinVar contains an entry for this variant (Variation ID: 12409). Different missense substitutions at this codon (p.Arg92Trp, p.Arg92Leu) are reported to be deleterious (PMID: 9060892, 16326803, 22144547). Functional studies have demonstrated that several substitutions between codons 91 and 110, including p.Arg92, impair tropomyosin-dependent functions of troponin T (PMID: 11606294) indicating that this missense change is located within a functionally conserved domain of the TNNT2 protein. This indicates that the arginine residue is important for TNNT2 protein function. Experimental studies have shown that this missense change results in an increase in Ca2+ sensitivity of force development (PMID: 10085122, 12186860). Although transgenic mice did not develop HCM, they showed increased cardiac contractility and histopathological findings consistent with HCM (PMID: 9788962, 10449439, 11158969). In summary, this rare missense variant has been found in multiple affected individuals, segregates with the disease and has been found to have an impact on protein function. For these reasons, it has been classified as Pathogenic.
Center for Medical Genetics Ghent,University of Ghent RCV000013220 SCV000299242 likely pathogenic Familial hypertrophic cardiomyopathy 2 2016-03-08 criteria provided, single submitter clinical testing This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with HCM. Studies have shown that the variant impacts protein function (PMID:8205619).
Ambry Genetics RCV000621709 SCV000735554 pathogenic Cardiovascular phenotype 2017-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes)
OMIM RCV000013220 SCV000033467 pathogenic Familial hypertrophic cardiomyopathy 2 1994-06-03 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000159281 SCV000280516 pathogenic not provided 2012-01-16 no assertion criteria provided clinical testing 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.

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