ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln) (rs200411226)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171824 SCV000054769 pathogenic Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168090 SCV000198912 pathogenic Hypertrophic cardiomyopathy 2019-07-20 criteria provided, single submitter clinical testing The p.Arg495Gln variant in MYBPC3 has been reported in >20 individuals with HCM and segregated with disease in 5 affected relatives from 3 families (Niimura 1998, Maron 2001, Van Driest 2004, Ehlermann 2008, Fokstuen 2008, Morita 2008, Millat 2010, Fokstuen 2011, Brito 2012 personal communication, Lopes 2013, Marsiglia 2013, Kapplinger 2014, Walsh 2017, LMM data). However, multiple unaffected relatives from different families also carried this variant, at least 6 of whom were over the age of 50 (Brito 2012, LMM data), suggesting reduced penetrance. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 164113) and has been identified in 5/112974 European chromosomes by gnomAD ( Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies suggest that carriers of this variant exhibit heightened expression of MYBPC3 as compared to controls, leading to an abundance of the mutant protein in cardiac tissue (Helms 2014). However, it is unclear how this would impact cardiac function. In addition, 2 different amino acid changes at this position (p.Arg495Gly and p.Arg495Trp) have been reported in multiple individuals with HCM (Niimura 1998, Maron 2001, García-Castro 2009, Martín 2009, Rodríguez-García 2010, Brito 2012, Coto 2012, Lopes 2013), suggesting that changes at this position are not tolerated. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner; however, it should be noted that penetrance may be reduced. ACMG/AMP Criteria applied: PS4, PM2, PP1_Moderate, PP3, PM5_supporting.
GeneDx RCV000223693 SCV000208030 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The R495Q pathogenic variant in the MYBPC3 gene has previously been reported in several unrelated individuals with HCM from various ethnic backgrounds (Niimura et al., 1998; Maron et al., 2001; Van Driest et al., 2004; Fokstuen et al., 2008; Ehlermann et al., 2008; Kaski et al., 2009; Brito et al., 2012; Lopes et al., 2013; Ng et al., 2013; Marsiglia et al., 2013; Mendes de Almeida et al., 2017; Walsh et al., 2017). Niimura et al. (1998) reported R495Q segregated with disease in three affected individuals from a family with HCM. Mendes de Almeida et al. (2017) also reported segregation with disease in two affected relatives with HCM, including one pediatric case. In addition, R495Q has been identified in multiple unrelated probands with HCM referred for genetic testing at GeneDx, and it was found to segregate with disease in affected relatives from multiple unrelated families. Of note, the R495Q variant has also been observed in asymptomatic relatives, both in the literature and at GeneDx, suggesting this variant may have reduced penetrance and exhibit a more mild effect (Morita et al., 2008; Christiaans et al., 2010; Millat et al., 2011).R495Q is not observed at a significant frequency in large population cohorts (Lek et al., 2015). This substitution occurs as a highly conserved residue which is located in the phosphorylation domain of the molecule (Niimura et al., 1998). Other pathogenic or likely pathogenic variants affecting this residue (R495G, R495W) have also been reported in association with HCM (Rodriguez-Garcia et al., 2010; Page et al., 2012; Zou et al., 2013; Captur et al., 2014), further supporting the functional importance of this residue. Finally, Helms et al. (2014) reported that R495Q mutant peptide was predominantly expressed compared to wild-type protein in heart tissue specimens from two HCM patients, though the precise correlation to phenotype is yet to be determined.
Invitae RCV000168090 SCV000218744 pathogenic Hypertrophic cardiomyopathy 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 495 of the MYBPC3 protein (p.Arg495Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs200411226, ExAC <0.01%). This variant has been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 11499718, 20019025, 22857948, 23396983, 24093860). This sequence change has been reported in a family affected with hypertrophic cardiomyopathy (HCM), where it segregated with disease in 3 individuals, and was present in 1 unaffected individual and in 2 with an indeterminate status (PMID: 9562578). ClinVar contains an entry for this variant (Variation ID: 164113). A different missense substitution at this codon (p.Arg495Gly) is reported to be deleterious (PMID: 18403758, 19659763, 20624503). This indicates that the p.Arg495 residue is important for MYBPC3 protein function. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare sequence change that has been observed in multiple HCM patients and affects a residue that is likely required for normal protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201509 SCV000256159 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000171824 SCV000264026 pathogenic Primary familial hypertrophic cardiomyopathy 2015-03-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000336189 SCV000372358 pathogenic MYBPC3-Related Disorders 2016-06-14 criteria provided, single submitter clinical testing Across a selection of the available literature, the c.1484G>A (p.Arg495Gln) variant has been reported in a heterozygous state in 18 patients with hypertrophic cardiomyopathy, one patient with left ventricular noncompaction cardiomyopathy, two individuals with an indeterminate status, and in a compound heterozygous state in one individual with hypertrophic cardiomyopathy (Niimura et al. 1998; Zeller et al. 2006; Ehlermann et al. 2008; Millat et al. 2010; Antonio et al. 2011; Marsiglia et al. 2013; Helms et al. 2014). The p.Arg495Gln was also found in a heterozygous state in one unaffected individual but was absent from 536 control chromosomes. The variant is reported at a frequency of 0.00001 in the European (Finnish) population of the Exome Aggregation Consortium but this is based on one allele so is presumed to be rare. Helms et al. (2014) demonstrated that heart tissue samples carrying the p.Arg495Gln variant exhibited higher MYBPC3 expression and transcript levels but no increase in protein abundance when compared to control heart tissues. MYBPC3 variants have displayed reduced penetrance and variable expressivity. Based on the collective evidence, the p.Arg495Gln variant is classified as pathogenic for MYBPC3-related disorders.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000168090 SCV000492795 likely pathogenic Hypertrophic cardiomyopathy 2015-09-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589860 SCV000696312 pathogenic Cardiovascular phenotype 2019-02-12 criteria provided, single submitter clinical testing Variant summary: The variant, MYBPC3 c.1484G>A (p.Arg495Gln) results in a conservative amino acid change located in the Immunoglobulin-like domain (Immunoglobulin subtype 2) and Immunoglobulin I-set domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250252 control chromosomes (gnomAD and publications) and has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (HCM, Marsiglia_2013, Lopes_2013). In one family, this variant cosegregates with HCM in three affected family members, however, one unaffected family member whose age was above the age of onset carried this variant implying reduced penetrance or later onset (Niimura_1998). Two co-occurrences with other likely pathogenic variants (MYBPC3 p.Tyr1172fs, TNNI3 Arg141Gln) have been reported in two HCM patients, respectively (Millat_2010, Morita_2008). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating the impact of the variant on protein function, does not allow convincing conclusions about the variant effect (Helms_2014). However, myocardial tissue obtained from a human HCM subject that harbors the variant show molecular signatures of aberrant calcium signaling (increased Ca2+/Calmodulin dependent protein kinase II (CaMKII) activation and reduced SERCA2 (Sarcoplasmic/endoplasmic reticulum calcuium ATPase 2) mRNA levels, (Helms_2016). Experimental evidence suggest that mutations causative of HCM in both thick and thin sarcomere filaments may lead to abnormal calcium handling and increase the risk of arrhythmia in HCM (Helms_2016). Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV000589860 SCV000739944 pathogenic Cardiovascular phenotype 2018-06-05 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Rarity in general population databases (dbsnp, esp, 1000 genomes)
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000201509 SCV000744850 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000223693 SCV000855753 likely pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763243 SCV000893879 pathogenic Familial hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000201509 SCV001150174 pathogenic Familial hypertrophic cardiomyopathy 4 2018-05-23 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000168090 SCV001156327 pathogenic Hypertrophic cardiomyopathy 2018-05-02 criteria provided, single submitter research The MYBPC3 Arg495Gln variant has been described in many HCM probands and has been reported to segregate with disease in several families (see literature). A study analysing the transcript and protein levels in two septal myectomy patients carrying the MYBPC3 Arg495Gln variant revealed that not only did the patients exhibit a 2-fold increase in MYBPC3 protein expression but were also found to predominately express the mutant peptide (Helms AS, et al., 2014), which is supportive of the pathogenic role of the variant. The variant is present at a low frequency in the Genome Aggregation Database ( We identified this variant in 2 HCM probands. One proband was diagnosed after they suffered resuscitated cardiac arrest in childhood, family screening identified an additional 3 affected family members in which the variant segregated (Ross SB, et al., 2017). The second proband does not have a family history of disease (Ingles et al., 2017). Interestingly, different rare variants at this position (Arg495Trp, Arg495Gly) have also been reported in HCM cases, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, PolyPhen2, and MutationTaster predict this variant to have a deleterious effect. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant has been reported in more than 15 HCM probands (PS4), segregates with disease in multiple families (PP1_strong), is rare in the general population (PM2) and in silico tools predict it to be deleterious (PP3), therefore we classify MYBPC3 Arg495Gln as "pathogenic".
CeGaT Praxis fuer Humangenetik Tuebingen RCV000223693 SCV001249486 pathogenic not provided 2018-01-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171139 SCV001333823 pathogenic Cardiomyopathy 2018-03-01 criteria provided, single submitter clinical testing
Color RCV001171139 SCV001360091 pathogenic Cardiomyopathy 2019-01-17 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000201509 SCV001428773 pathogenic Familial hypertrophic cardiomyopathy 4 2019-10-07 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223693 SCV000280212 likely pathogenic not provided 2015-03-17 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. MYBPC3 p.Arg495Gln We first reviewed the variant in October 2013. We re-reviewed it October 15th, 2015 and found even stronger data in favor of pathogenicity. The variant has been seen in at least 25 unrelated cases of HCM (not including this patient) with some segregation data in one family. ~10 of these cases may be attributable to a Brazilian founder. Niimura et al. (1998, Seidman group) reported this variant in an individual with HCM within a cohort of 16 families. Three affected family members all had the variant as did two individuals with indeterminate phenotype (described by the authors as left ventricular hypertrophy with confounding factors such as hypertension). Same family is also included in a later paper by the same group (Maron B et al. 2001). Van Driest et al (2004) identified this variant in one patient in a cohort of 389 unrelated patients with HCM at Mayo clinic. No information is given on the patient's phenotype. They report no segregation data. Ehlermann (2008) observed this variant in one HCM patient from a cohort of 87 patients with HCM. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. There is no specific reported clinical data on the patient with this variant. Morita et al. (2008) reported this variant in an individual with HCM while looking at a cohort of 84 children with idiopathic cardiac hypertrophy diagnosed before age 15. This individual also carried TNNI3 Arg141Gln (which we classify as likely disease causing) in addition to the MYBPC3 Arg495Gln variant. No segregation data or parental data was included. Individual phenotypic details were not provided (though onset was pediatric in all cases). Frisso et al (2009) report a patient with HCM from their Italian cohort who underwent analysis of 8 sarcomere genes. He was diagnosed at 2 years of age and his father had left ventricular non-compaction and also carried the variant. Kaski et al (2009, McKenna's group) observed this variant in one patient in a cohort of 79 patients diagnosed with HCM at age 13 years or younger from London. They did not give specific data regarding the patient with this variant nor segregation data. This could overlap with a later report from the same group (Captur et al 2014). Marsiglia et al (2013) observed the variant in 10 of 268 unrelated HCM patients from their Brazilian cohort who underwent sequencing of MYH7, MYBPC3, TNNT2. Ackerman's group observed the variant in 7 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and perhaps also with internal data from genetic testing labs. Sharlene Day's group included two unrelated HCM patients with this variant in a recent paper on transcription levels in MYBPC3 carriers (Helms et al 2014). That case may overlap with internal data from clinical labs. We have seen the variant in one other patient with HCM in our center. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The arginine at codon 495 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg495Trp, Arg495Gly) and nearby codons (Thr494lle; Gly490Arg). Niimura notes that this variant is in the 244-amino acid segment that spans the phosphorylation domain of the molecule. Helms et al (2014) observed an increase in expression of the mutant peptide in heart tissue of two unrelated HCM patients with this variant. In total the variant has not been seen in ~8,000 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 495 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/15/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/15/13). The variant was not observed in the following laboratory and published control samples: Familion internal control population of over 400 unrelated, ethnically diverse, presumed healthy individuals. Kaski et al did not observe this variant in 200 presumed healthy controls. Morita reports this variant was absent in 180 unrelated persons matched by ancestral origin to the subjects and in more than 1000 chromosomes of unaffected persons. Van Driest reported this variant was not present in 400 reference alleles (200 from ethnically matched Caucasian Americans, and 200 from ethnically diverse African Americans; same as Bos et al 2014).

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