ClinVar Miner

Submissions for variant NM_000364.3(TNNT2):c.853C>T (p.Arg285Cys) (rs121964857)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000159322 SCV000605411 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing The p.Arg278Cys variant (rs121964857) has been extensively reported in association with hypertrophic cardiomyopathy (HCM; first reported in Watkins 1995). However, the exact contribution of this variant to the development of HCM is currently under debate. For example, this variant is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 12411), with multiple clinical labs noting incomplete segregation/penetrance of this variants in familial studies (Garcia-Castro 2003, Theopistou 2004, Gimeno 2009, Ripoll-Vera 2016), and that multiple patients analyzed have additional clinically relevant variants in other HCM-related genes; an observation that has as has also been reported in the literature (Gimeno 2009 and Garcia-Castro 2009). Additionally, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.06% (identified in 74 out of 123,324 chromosomes). However, this relatively high population frequency, while disqualifying this variant as a high penetrance, early onset disease allele, would be consistent with a late onset/low penetrance model of disease etiology (see case report in Elliott 1999 for example of late onset disease in a carrier). Functional studies using isolated muscle fibers show subtle, but reproducible, changes in force generation caused by the p.Arg278Cys variant (Yanaga 199, Szczesna 2000, and Hernandez 2005). However, whether these defects in vitro are relevant to disease manifestation in human patients is not completely understood. Taken together, the clinical significance of the p.Arg278Cys variant cannot be determined with certainty. And at most, the genetic evidence is is consistent with this variant being a low penetrance risk factor or genetic modifier of more penetrant alleles.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162331 SCV000212627 uncertain significance Familial hypertrophic cardiomyopathy 1 2014-09-10 criteria provided, single submitter research This TNNT2 Arg278Cys variant has been described in multiple HCM cohorts (see references) and in genetic screening of one DCM cohort (Millat G. et al., 2011). Segregation with disease has been shown where familial screening was available, though incomplete disease penetrance was observed (Gimeno JR, et al., 2009; García-Castro M, et al., 2007; Miliou A. et al., 2005; Theopistou A. et al., 2004; Watkins H, et al. 1995). The disease phenotype is variable. This mutation has been characterised by late-onset disease with mild hypertrophy but with a high incidence of sudden death. However, severe disease presentation including cardiac arrest events have been reported in young patients (Miliou A. et al., 2005; Theopistou A. et al., 2004; Watkins H. et al., 1995), including one paediatric HCM case (Kaski JP. et al., 2009). It should be noted that genetic analysis of the majority of these studies was limited to a small number of genes, and that additional mutations in other disease causing genes cannot be excluded in these patients. Studies by Gimeno JR. et al (2009) and Kaski JP. et al (2009) report carriers of the TNNT2 Arg278Cys mutation who also have a secondary mutation in another sarcomere gene present with moderate to severe phenotypes. Transgenic mouse models of this mutation did not develop significant hypertrophy or fibrosis (Hernandez OM. et al., (2005), however in vitro functional assays indicate that the mutation affects muscle contraction (Takahashi-Yanaga F. et al., 2001; Morimoto S. et al., 1999). We have detected this variant in 3 unrelated families in our cohort, though 2 families carry an additional "likely pathogenic" or "pathogenic variant" in another known HCM causing gene. Based on the current literature and our data, this variant in isolation may cause a mild phenotype, however further evidence is required to fully establish its role in disease pathogenicity.
Ambry Genetics RCV000248304 SCV000318976 likely pathogenic Cardiovascular phenotype 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
Blueprint Genetics, RCV000157540 SCV000207286 uncertain significance Costello syndrome 2013-08-28 no assertion criteria provided clinical testing
Blueprint Genetics, RCV000159322 SCV000927753 uncertain significance not provided 2018-06-15 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148898 SCV000190644 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Center for Human Genetics,University of Leuven RCV000768493 SCV000886798 likely pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000159322 SCV000511738 uncertain significance not provided 2016-07-29 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Color RCV000771167 SCV000903051 uncertain significance Cardiomyopathy 2018-10-08 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the tropomyosin binding domain near the C-terminal end of the TNNT2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. In vitro experimental studies have shown that this variant increases Ca2+ sensitivity and leads to abnormal myosin cross-bridges (PMID: 10085122, 10405326, 10617660, 11432788, 21683708, 22500102, 24418317). However, these results were not reproduced in transgenic mice, which did not show Ca2+ sensitivity, ventricular fibrosis or significant hypertrophy (PMID: 19033660, 16115869, 16777946). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 7898523, 10610467, 12860912, 14636924, 15246915, 15958377, 16199542, 16715312, 20031618, 25611685, 26507537). Two of these patients also carried pathogenic variants in MYBPC3 and MYH7, respectively (PMID 26507537). Segregation analysis in families has yielded inconclusive results (PMID 14563299, 15958377, 25524337). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 21846512, 24503780) and arrhythmia (PMID: 26743238). This variant has also been identified in 95/270138 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the inconclusive segregation analysis, co-occurrence with other disease-causing variants, elevated allele frequency in the general population and conflicting experimental data, the clinical significance of this variant is uncertain.
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755702 SCV000883136 uncertain significance Left ventricular noncompaction 6 2018-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000159322 SCV000209268 likely pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The R278C likely pathogenic variant in the TNNT2 gene has been reported multiple times in association with HCM (Watkins et al., 1995; Garcia-Castro et al., 2003; Torricelli et al., 2003; Van Driest et al., 2003; Theopistou et al., 2004; Ingles et al., 2005; Gimeno et al., 2009; Millat et al., 2011; Brito et al., 2012; Ripoll-Vera et al., 2016). The R278C variant is reported to segregate with disease in a number of families (Garcia-Castro et al., 2003; Theopistou et al., 2004; Gimeno et al., 2009). However, some individuals with cardiomyopathy who carried the R278C variant were found to also harbor variants in the MYH7 and MYBCP3 genes (Gimeno et al., 2009; Ripoll-Vera et al., 2016), and individuals with only the R278C variant demonstrated milder cardiac hypertrophy and incomplete penetrance (Gimeno et al., 2009). Additionally, the R278C variant has been identified in multiple other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, some of whom also harbor pathogenic or likely pathogenic variants in other genes associated with cardiomyopathy.Nevertheless, Hernandez et al. (2005) reported that cardiac fibers from mice with the R278C variant demonstrated a significant decrease in force, although ATPase activity remained stable, resulting in more energy used for muscle contraction. The authors suggest that this decrease in force and increase in energy cost may be a factor in triggering hypertrophy in humans (Hernandez et al., 2005). Another functional study demonstrated that R278C results in increased calcium ion sensitivity of force development, which alters contractility and may contribute to the development of HCM (Szczesna et al., 2000). Yanaga et al. (1999) also found R278C to have a calcium ion sensitizing effect, without inducing any change in maximum ATPase activity.The R278C variant was absent from 700 published control alleles, collectively (Ingles et al., 2005; Millat et al., 2011). However, the R278C variant is observed in 74/123324 (0.06%) alleles from individuals of European (non-Finnish) background (Lek et al., 2016). Nevertheless, a likely pathogenic missense variant at the same residue (R278P) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this residue. Located in the binding site of the TPM1 and troponins I and C, R278C 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. This substitution occurs at a position that is conserved in mammals; however, cysteine is tolerated at this position in at least one mammalian species.Furthermore, despite the fact that several publications describe an association between the R278C variant in the TNNT2 gene and HCM, family history information and segregation data is not sufficient to classify this variant as pathogenic.
Invitae RCV000203739 SCV000261146 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-06-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 278 of the TNNT2 protein (p.Arg278Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121964857, ExAC 0.06%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 7898523, 12860912, 14636924, 15246915, 15958377, 16199542, 21846512, 26507537) and dilated cardiomyopathy or other cardiomyopathy (PMID: 24503780, 26743238). It has been shown to segregate with disease although with reduced penetrance (PMID: 15958377, 25524337); however, lack of segregation was also observed in one independent family (PMID: 14563299). Furthermore, in at least two individuals affected with HCM this variant was found to co-occur with a pathogenic variant in a different gene, suggesting that Arg278Cys was not the primary cause of disease (PMID: 26507537). ClinVar contains an entry for this variant (Variation ID: 12411). Experimental studies have shown conflicting results on the functional impact of this variant. It has been shown that this variant increases Ca2+ sensitivity and leads to abnormal myosin cross-bridges (PMID: 10085122, 10405326, 10617660, 11432788, 21683708, 22500102, 24418317). However, these results did not replicate in transgenic Cys278 mice (PMID: 19033660, 16115869, 16777946). In summary, this variant is a rare missense change that has been reported in several individuals affected with HCM. However, it has been shown to co-occur with pathogenic variants in several affected individuals, and segregation and functional data are inconclusive. Furthermore, this variant is found in the population at an appreciable frequency and therefore is not anticipated to cause disease. For these reasons, this variant has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036622 SCV000060277 uncertain significance not specified 2017-08-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg278Cys variant in TNNT2 has been reported in >10 individuals with HCM and segregated with disease in at least 5 affected individuals (including one affected obligate carrier) from multiple families*. This variant has been identified by our laboratory in many individuals with HCM (mainly Caucasian), though approximately half of them carried a second clinically significant variant in another gene. Many affected individuals carrying the p.Arg278Cys variant present at age 50 or older, suggesting a milder effect (LMM data). This variant has also been identified in 74/123324 of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs121964857). Computational evidence is somewhat conflicting as the affected amino acid is incompletely conserved but the variant is predicted to be pathogenic using a computational tool clinically validated by our laboratory (pathogenic predictions are estimated to be correct 94% of the time; Jordan 2011). Functional studies indicate it may affect muscle contraction**, although in vitro assays may not accurately represent biological function. In summary, while there is suspicion of a pathogenic role, likely with a milder effect when present in isolation, the clinical significance of this variant is uncertain. This variant should be interpreted carefully in the context of the individual’s age at onset. *(Watkins 1995, Elliott 1999, Garcia-Castro 2003, Torricelli 2003, Van Driest 2003, Theopistou 2004, Ingles 2005, Zeller 2006, Garcia-Castro 2009, Kaski 2009, Gimeno 2009, Millat 2010, Brito 2012, Rubattu 2016, LMM data). **(Morimoto 1999, Yanaga 1999, Szczesna 2000, Hernandez 2005).
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000148898 SCV000747995 pathogenic Primary familial hypertrophic cardiomyopathy 2017-07-20 criteria provided, single submitter clinical testing
OMIM RCV000013222 SCV000033469 pathogenic Familial hypertrophic cardiomyopathy 2 1999-07-22 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000036622 SCV000280532 uncertain significance not specified 2013-05-23 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. p.Arg278Cys in TNNT2 This variant was recently reviewed in detail for one of our research projects. Based on the presence in the general population and the fact that many cases carry an additional pathogenic variant, we would consider this variant a variant of uncertain significance, possibly a modifier. TNNT2 gene p.Arg278Cys (c.832C>T) Summary: -Seen in at least 51 presumably unrelated cases of HCM (26 published, >25 unpublished). -most had European ancestry (at least 30 out of 51); ancestry for others was not reported. -Also seen in DCM cases. -14 of 47 cases who had sequencing of at least MYH7 and TNNT2 had another variant. -5/14 are likely pathogenic/pathogenic, while 4/14 are VUS; 5/14 variant details were not available to confirm the classifications. -60-year-old European (Spain) female with HCM had additional variant in MYBPC3 gene (p.Arg733His) (ClinVar: VUS by GeneDx) -50-year-old European (Spain) female with HCM (LVWT of 22 mm) and her 2 affected family members carried additional variant in MYH7 (p.Asp928Asn) (ClinVar: likely pathogenic by LMM; pathogenic by GeneDx) -14-year-old European (France) individual carried a second variant in MYBPC3 (p.Asp610His) (ClinVar: VUS by LMM) -30.5-year-old HCM case (LVWT of 24 mm) had an additional variant in MYBPC3 (p.Asp560Thrfs*19) (classified as likely pathogenic by LMM) -49-year-old female of unreported ancestry with HCM (LVWT of 35) had an additional variant in MYBPC3 (p.Arg1781His) (ClinVar: VUS by LMM) -46.5-year-old European (Italy) proband with HCM (LVWT of 28 mm) and one affected family member carried a second variant in MYBPC3 gene (p.Thr1095Met) (ClinVar: not found; likely pathogenic by Florence). -56-year-old European (Italy) proband with HCM (LVWT of 18 mm) carried a second variant in MYBPC3 (p.Lys814del) (ClinVar: not found; pathogenic by Florence) -34-year-old female of unreported ancestry with HCM carried an additional variant in the MYBPC3 gene (IVS11-9G>A; c.927-9G>A) (Helms et al (2014): pathogenic based on splice site functional studies) -15-year-old of unreported ancestry with HCM (LVWT of 38) carried an additional variant in the in MYBPC3 gene (p.Ala848Gly) (ClinVar: VUS by GeneDx) -There is some segregation data. In three families, four affected relatives (in addition to probands) carried this variant and one had SCD. In two other families, four affected relatives (in addition to probands) carried p.Arg278Cys in addition to another variant. -In total, the variant has been seen in 40 of ~48,482 individuals (0.08%) from published controls and publicly available datasets that approximate the general population. Most were European ancestry (33 out of 28,255 individuals). In ExAC the highest MAF was 0.06% (33/26987 Europeans). Published cases: Watkins et al (1995) first reported the variant in a 17-year-old female who had normal left ventricular thickness yet had suffered a cardiac arrest; she was resuscitated. The ethnicity of the proband was not reported. Probands included 16 from Europe, 4 from North America, 3 from Japan, and 1 each from China, Southeast Asia, and Pakistan. While this one case is somewhat concerning for an increased risk of sudden death conferred by this variant, other reported cases have had more typical HCM courses, consistent with the marked variable expressivity often seen in primary cardiomyopathies. Elliott et al (1999) reported the variant in a 57-year-old male of unreported ancestry with HCM who was treated at St. George’s Hospital Medical School, London. The genes analyzed were not reported. The proband presented with syncope and dyspnea at the age of 54 years, and was found to have a septum of 12 mm, a left ventricular outflow tract (LVOT) gradient, and systolic anterior motion (SAM) of the mitral valve at 57 years. His grandfather had died suddenly at the age of 60 years. No additional variants were reported. Van Driest et al (2003) observed the variant in three of 389 unrelated patients of unreported ancestry diagnosed with HCM that were cared for at Mayo Clinic’s HCM Clinic in Rochester, Minnesota. The cohort underwent an analysis of TNNT2, TNNI3, TPM1, and ACTC genes. The first proband, a male diagnosed with HCM at age of 54 years with no family history of HCM, presented with LVWT of 20 mm. The second proband, a male diagnosed with HCM at 31 years with family history of HCM, presented with angina, dyspnea, atrial fibrillation, LVWT of 15 mm, and needed a pacemaker. The third proband, a male diagnosed at age 69 year with no family history of HCM, presented with dyspnea, LVWT of 23 mm, and required a septal ablation. No additional variants were reported. Garcia-Castro et al (2003) reported this variant in a 60-year-old female, one of 30 European (Spanish) HCM cases who underwent analysis of the MYH7 and TNNT2 genes. She was diagnosed at age 49 with asymmetric septal hypertrophy and had a history of syncope, dyspnea, dizziness, palpitations, and an LVWT of 22 mm. In 2009, Garcia-Castro et al reported an additional variation in this proband in the MYBPC3 gene (c.2198G>A; p.Arg733His), which is reported as a VUS by GeneDx in ClinVar (as of Aug 29, 2011). They reported that her double heterozygote daughter (40 years old) and granddaughter (6 years old) were “asymptomatic” (no mention of echo phenotyping). Proband’s older 52-year-old sister had mild hypertrophy (LVWT of 13 mm) and carried only p.Arg278Cys. Torriceli et al (2003) reported this variant in one of 150 unrelated HCM patients with European ancestry (Italian) that were cared for at Azienda Ospedaliera Careggi, who underwent the analysis of the MYH7, MYBPC3, TNNT2, and MYL2 genes. This was a 62-year-old male who had an LV thickness of 24 mm, needed percutaneous septal ablation and had no family history of hypertrophic cardiomyopathy. No additional variants were reported. Theopistou et al (2004) reported this variant in two probands with HCM from two families of European ancestry (Greek), who underwent analysis of the TNNT2 gene. In one family, the proband was diagnosed with HCM and a septum of 22 mm at 13 years of age. He died suddenly at 15. His sibling and parents all had normal echocardiograms, and did not have genetics evaluation. In the other family, the proband, 40-year-old male diagnosed at the age of 33 years with LVWT of 22, had family history of sudden death and HCM. His mother had sudden death (no genetics evaluation), and his maternal aunt, who was diagnosed with HCM at 64 years with LVWT of 15 mm, tested positive for this variant. Three members of his family with the variant had normal echocardiograms at 14, 38, and 42 years of ages. No additional variants were reported for either family. Ingles et al (2005) reported this variant in one out of 80 Australian HCM cases. MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3 were evaluated and no other variants were found for this proband. No phenotypic information specific to this proband was provided by the authors. Zeller et al (2006) reported this variant in one of 30 European (German) HCM cases. No additional variants were found in any of the following genes: ACTC, ALP, CAPZB, CARP, DES, DMN, FKRP, FLT1, GJA1, JUP, LDB3, LMNA, MYBPC3, MYH7, MYOZ2, MYPN, NCK2, PLCG1, PXN, SGCD, TNNT2, TPM1, TPM2, TTID, and VEGF. No phenotypic information specific to this proband or additional variants were reported by the authors. Kaski et al (2009) reported this variant in one out of 79 cases with HCM. The ethnicity of the proband was not reported. No additional variants were found in any of the following analyzed genes: MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC, TNNC1, DES, and PRKAG2. The cohort comprised of 89.9% white, 3.8% Asian, 2.5% black, 2.5% Middle Eastern cases. All of the HCM cases were diagnosed under the age of 13 years. No phenotypic information specific to this proband was provided by the authors. Gimeno et al (2009) reported this variant in two probands with HCM from two families of European ancestry (Spanish). Of note, this report appears to be distinct from those by Garcia-Castro et al. The first proband, female diagnosed at the age of 50 years with LVWT of 22 mm, had two affected family members that carried this variant. Her brother was diagnosed at 18 years with LVWT of 22 mm who presented with palpitations and dyspnea, and her nephew (affected brother’s son) was diagnosed at the age of 18 with LVWT of 40 mm who presented with presyncope. The following genes were analyzed in this family: TNNT2, MYH7, MYBPC3, TPM1, ACTC, TNNI2, TNNC1, MYL2, MYL3. All three of the affected members of this family carried an additional variation in MYH7 gene (c.2782G>A; p.Asp928Asn), which is classified as likely pathogenic and pathogenic by LMM (Aug 26, 2014) and GeneDx (Mar 15, 2014) in ClinVar, respectively. Of note, the proband’s affected son who carried the MYH7 gene variant, but did not carry the TNNT2 variant. The second proband was a male diagnosed at the age of 59 years with 26 mm LVWT, persistent atrial fibrillation, and palpitations. No additional variants were reported for this proband. They report that his 33yo son carries the variant, has LVWT of 1.1 cm and a Brugada pattern on ECG. Millat et al (2010) reported this variant in 4 out of 192 unrelated HCM cases of European ancestry (French) who underwent analysis of MYH7, MYBPC3, TNNT2, and TNNI3 genes. One of the 4 variant carriers, diagnosed at the age of 14, also carried a second variant in the MYBPC3 gene (p.Asp610His), which is classified as a VUS by LMM in ClinVar (Sep 28, 2011). No phenotypic information specific to this proband was provided by the authors. Gruner et al (2011) reported this variant in 1 out of 61 unrelated patients with apical HCM and 3 out of 365 unrelated nonapical HCM cases. Ethnicity of these probands was not reported, however the majority of the cohort had European ancestry (312/425). The proband with apical HCM was a 50-year-old male with maximal wall thickness of 16 mm and syncope. He has no family history of HCM or SCD. One of the 3 nonapical HCM probands had a family history of SCD. No additional variants were reported for these probands after analyzing the following genes: MYBPC3, MYH7, MYL2, MYL3, TNNT2, TNNI3, TPM1, ACTC, GLA, LAMP2, PRKAG2, and PRKAG2. Millat et al (2011) reported this variant in 1 out of 105 unrelated European (French) cases with dilated cardiomyopathy, who underwent analysis of the MYH7, TNNT2, TNNI3 and LMNA genes. The proband was a 69-year-old female with LVEDD of 65 mm, syncope, atrial fibrillation, and NYHA class III (LVWT was not reported). She has at least two family members diagnosed with DCM but no molecular data available on them. Brito et al (2011) reported this variant in a mother and daughter out of 77 unrelated European (Portuguese) cases with HCM, who underwent analysis of MYBPC3, MYH7, TNNT2, TNNI3 and MYL2 genes. In addition, there was a family history of sudden death in a first-degree relative (aged <50 years). No additional variants were reported in this family. Nunez et al (2013) reported this variant in one out of 104 European (Spanish and English) patients with sporadic HCM who underwent analysis of MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 genes. No additional variants were reported in this proband. No phenotypic information specific to this proband was provided by the authors. The variant Additional data: In-silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 278 is not well conserved in evolution and 2 species (elephant, manatee) carry a cysteine at this position. Other variants have been reported in association with disease at this codon: p.Arg278Pro (Van Driest et al, 2003). In addition, the following variants in nearby codons have been associated with HCM: p.Lys273Glu (Fujino, 2002), p.Arg286Cys (Richard, 2003), p.Arg286His (Van Driest, 2003). Functional studies by Yanaga et al (1999) indicate that p.Arg278Cys causes an increase in Ca2+ sensitivity therefore increasing the contractility of the cell and inducing hypertrophy. Frequency in controls, large cohorts unselected for HCM: In total the variant has been seen in 40 of 48,482 (0.08%) laboratory controls, published controls and individuals from publicly available population datasets. The variant was reported online in 33 of 26,987 European ancestry individuals (0.12%) and 3 of 4,095 African-American individuals in the ExAC Browser dataset (as of 5/1/15). None were selected for rare inherited cardiomyopathies and in some cases those phenotypes were excluded. However, the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant was not observed in 1818 European and 100 African ancestry individuals across the following published studies in presumably healthy controls: 100 in Watkins (1995), 200 in Van Driest (2003), 200 in García-Castro (2003), 150 in Torriceli (2003), 100 in Miliou (2005), 150 in Ingles (2005), 168 in Zeller (2006), 200 in Kaski (2009), 200 in Millat (2010), 200 in Millat (2011), and 200 in Nunez (2013).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.