ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.304C>T (p.Arg102Trp) (rs397516456)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000768491 SCV000060228 pathogenic Hypertrophic cardiomyopathy 2015-04-01 criteria provided, single submitter clinical testing The p.Arg92Trp variant in TNNT2 has been reported in the literature and by our l aboratory in >20 individuals with HCM and segregated with disease in >15 affecte d relatives from >5 families (Koga 1996, Ackerman 2002, Moolman 1997, Moolman-Sm ook 1999, Fujino 2001, Varnava 2001, Van Driest 2003, Marsiglia 2010, Yang 2011, Fujita 2013; LMM unpublished data). This variant has been identified in 1/66730 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs397516456). Please note that for diseases with clini cal variability or reduced penetrance, pathogenic variants may be present at a l ow frequency in the general population. In vitro functional studies and mouse mo dels provide evidence that the p.Arg92Trp variant impacts protein function (Palm 2001, Harada 2004, Ertz-berger 2005, Manning 2012). In summary, this variant me ets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon segregatio n studies and functional evidence.
GeneDx RCV000159280 SCV000209226 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing The pathogenic R92W variant in the TNNT2 gene has been reported multiple times in association with HCM (Koga et al., 1996; Moolman et al., 1997; Moolman-Smook et al., 1999; Palm et al., 2001; Van Driest et al., 2003; Revera et al., 2008; Ho et al., 2016; Ripoll-Vera et al., 2016). Moolman et al. (1997) and Koga et al. (1996) show the variant segregating with disease in multiple large families. Of note, Moolman et al. (1997) characterized the clinical phenotype in two families as minimal LVH with low penetrance, but with a high incidence of sudden cardiac death. Whereas, Koga et al. (1996) reports two families in which five affected relatives had a HCM phenotype and harbored R92W. Van Driest et al. (2003) reported R92W in a female with a clinical diagnosis of HCM at 18 years of age and a positive family history. Additionally, Ripoll-Vera et al. (2016) reported R92W in 10 families with cardiomyopathy and concluded that the R92W variant is associated with a mixed cardiomyopathy phenotype, early age of onset, high penetrance, and high risk of defibrillator implantation and sudden death. This variant has also been identified in several individuals referred to GeneDx for HCM genetic testing, and has been classified as a pathogenic variant by other clinical laboratories (ClinVar SCV000220080.1; SCV000264252.1; SCV000060228.4; Landrum et al., 2016). Furthermore, functional studies indicate R92W disrupts tropomyosin binding and increases calcium sensitivity of the cardiac thin filament (Palm et al., 2001, Revera et al., 2008, Manning et al., 2012a, Mannig et al., 2012b).
Blueprint Genetics RCV000208103 SCV000264252 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-05 criteria provided, single submitter clinical testing
Invitae RCV000474512 SCV000541909 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 92 of the TNNT2 protein (p.Arg92Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs397516456, ExAC 0.001%). This variant has been reported in dozens of individuals from multiple families affected with hypertrophic cardiomyopathy (PMID: 9060892, 8951566, 26507537). ClinVar contains an entry for this variant (Variation ID: 43627). Experimental studies have shown that this missense change results in an increase in Ca2+ sensitivity of force development (PMID: 14722098, 22334656). A different missense substitution at this codon (p.Arg92Gln) has been determined to be pathogenic (PMID: 7898523, 8205619, 9201030, 10085122, 10617660, 14722098, 18403758). This suggests that the arginine residue is critical for TNNT2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620701 SCV000739951 pathogenic Cardiovascular phenotype 2017-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,Other strong data supporting pathogenic classification
Center for Human Genetics,University of Leuven RCV000768491 SCV000886796 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000159280 SCV000928144 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000159280 SCV000280515 pathogenic not provided 2014-07-02 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. TNNT2 Arg92Trp (R92W; at the nucleotide level) This variant has been reported in at least 16 unrelated cases of HCM with good segregation data in 2 families and weak segregation data in two more. Strong functional data is available both in vitro and in a transgenic mouse model. Koga et al. (1996) found Arg92Trp in two Japanese HCM families. The variant was “present in all affected family members” (a total of 5 people), but specific segregation data for each family is not provided. Moolman et al. (1997) detected this variant in 2 South African families of mixed ancestry with HCM. Segregation data was available for one of these families, with five affected family members carrying the variant. Moolman-Smook et al. (1999) detected it in 4 additional HCM probands of mixed ancestry from South Africa. Varnava et al. (2001) detected it in 2 unrelated cases. Fujino et al. (2001)/Shimizu et al. (2003) identified it in 2 Japanese families. In one family, Arg92Trp segregated with disease in 6 affected family members (5 siblings and one of their children). In the other, two affected siblings carried the variant. Ackerman et al. (2002) detected it in one HCM patient at the Mayo Clinic; it segregated with disease in the patient and her mother. Waldmuller et al. (2002) used this variant in developing a microarray screen for recurring HCM variants. Van Driest et al (2003) detected it in another HCM case at the Mayo Clinic. Van Driest et al. (2004) reported a double-heterozygote carrying Arg92Trp plus a Val256Ile variant in MYBPC3. Konno et al. (2005) detected it in 8 Japanese individuals from HCM families (it is not clear if they are related, or how many have LVH).***note that the cases reported in Van Driest et al (2003, 2004) and Ackerman et al (2002) may overlap. Some authors have suggested that p.Arg92Trp in TNNT2 is associated with a higher risk of sudden death with mild or even absent hypertrophy (Moolman et al 1997, 1999). Two other mutations at the same codon have also been reported in families with HCM: p.Arg92Leu and p.Arg92Gln (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). 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. Harada & Potter (2004) showed the Arg92Trp variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. He et al. (2007) showed that transgenic mice bearing the Arg92Trp or Arg92Leu variant had a greater “energy cost” for cardiac muscle contraction than wild-type mice. The magnitude of these changes was mutation-specific: Arg92Trp hearts showed more severe energetic abnormalities and greater contractile dysfunction than Arg92Leu hearts. Guinto et al. (2009) showed diastolic dysfunction in transgenic mice carrying the variant, and altered calcium kinetics in isolated transgenic myocytes. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Tryptophan. 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 ~5990 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 ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Koga et al. (1996) did not detect the variant in more than 100 Japanese controls. Moolman et al. (1997) reported that the variant was absent from 100 control individuals. Moolman-Smook et al. (1999) did not find it in 100 controls (unclear if these were the same controls as in 1997). Fujino et al. (2001) did not detect it in 100 controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Van Driest et al. (2003) did not detect it in 100 Caucasian and 100 African American controls.

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