ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1504C>T (p.Arg502Trp) (rs375882485)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000223898 SCV000604327 pathogenic not provided 2017-06-22 criteria provided, single submitter clinical testing The p.Arg502Trp variant (rs375882485) is a well-known causative variant reported in multiple individuals with hypertrophic cardiomyopathy (HCM; Richard 2003, Maron 2008, Kaski 2012, and Lopez 2013), and shown to segregate with disease in at least one affected family (Camuglia 2013). In one large study, the p.Arg502Trp variant was identified in 2.4% of Caucasian HCM patients (Saltzman 2010). Nuclear magnetic resonance studies indicate that p.Arg502Trp may impair important electrostatic interactions between MYBPC3 protein and other sarcomeric proteins (Zhang 2014). Thus, the p.Arg502Trp variant meets our criteria for classification as pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584810 SCV000692517 pathogenic Familial hypertrophic cardiomyopathy 1 2017-03-16 criteria provided, single submitter research The MYBPC3 Arg502Trp s a well known cause of HCM, being reported in multiple HCM cases worldwide and segregating with HCM in families (see Ross et al. Circulation CV Genetics, 2017). The variant is present in the Exome Aggregation Consortium dataset (MAF=0.000025; We have identified this variant in 14 HCM families with some segregation data (total of 7 meiosis). Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, based on segregation, extensive reports of HCM cases with the variant and rarity in the general population, we classify MYBPC3 Arg502Trp as "Pathogenic".
Ambry Genetics RCV000252398 SCV000319017 pathogenic Cardiovascular phenotype 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position
Athena Diagnostics Inc RCV000223898 SCV000614141 likely pathogenic not provided 2016-12-16 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000035406 SCV000190379 pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000223898 SCV000862304 pathogenic not provided 2018-07-10 criteria provided, single submitter clinical testing
GeneDx RCV000223898 SCV000208031 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing The R502W pathogenic variant in the MYBPC3 gene has been reported multiple times in association with HCM (Richard et al., 2003; Van Driest et al., 2004; Ingles et al., 2005; Saltzman et al., 2010; Page et al., 2012; Lopes et al., 2013). This variant has also been observed in multiple unrelated individuals tested for HCM at GeneDx. Richard et al. (2003) identified the R502W variant in one patient with HCM and it was not present in 200 control chromosomes. This study also considered R502 a hot spot" for pathogenic variants because another variant affecting the same residue (R502Q) has also been associated with HCM (Richard et al., 2003; Niimura et al., 1998). Ingles et al. (2005) and Van Driest et al. (2004) observed the R502W variant in one HCM patient each, and the latter publication indicated R502W was not observed in 400 normal control alleles. Page et al. (2012) identified the R502W variant in nine families with HCM, in which variable penetrance and expressivity was observed. This pathogenic variant is observed at a low frequency in large population cohorts, reported in 13/126,700 (0.01%) alleles from individuals of European (non-Finnish) ancestry (Lek et al., 2016). R502W results in a non-conservative amino acid change of a positively charged Arginine residue with a non-polar Tryptophan residue at a position that is highly conserved across species. Functional studies by Zhang et al. (2014) suggested that R502W alters the electrostatic properties of the C3 domain which may disrupt the interaction with other sarcomeric proteins."
GenomeConnect, ClinGen RCV000203913 SCV000606931 not provided Hypertrophic cardiomyopathy no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000677196 SCV000803346 pathogenic Familial hypertrophic cardiomyopathy 4 2018-02-27 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000677196 SCV000840016 pathogenic Familial hypertrophic cardiomyopathy 4 2017-05-11 criteria provided, single submitter clinical testing This c.1504C>T (p.Arg502Trp) variant has been reported in multiple patients with hypertrophic cardiomyopathy (HCM) [PMID 1270723, 22589294, 23396983, 20378854, 23642604]. The variant was detected in 34 individuals from a large study of 1,414 unrelated HCM patients [PMID 20378854]. From this study, it was estimated that this variant conveys a 340-fold increased risk for HCM by 45 years and the clinical prognosis worsens when this c.1504C>T (p.Arg502Trp) change occurs in the setting of a pathogenic variant in another sarcomere protein gene [PMID 20378854]. This variant is common among HCM patients, occurring in an estimated 2.4% of patients [PMID 20378854]. This variant was reported in 3 heterozygous individuals in the ExAC database ( Arginine at position 502 of the MYBPC3 protein is highly conserved in mammals. While not validated for clinical use, computer-based algorithms predict this p.Arg502Trp change to be deleterious. This variant is thus classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000351173 SCV000372355 uncertain significance Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000403323 SCV000372356 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778104 SCV000372357 pathogenic MYBPC3-Related Disorders 2018-05-07 criteria provided, single submitter clinical testing The MYBPC3 c.1504C>T (p.Arg502Trp) missense variant is well documented as a pathogenic variant for hypertrophic cardiomyopathy (HCM). Across a selection of the available literature, the p.Arg502Trp variant has been identified in heterozygous state in at least 44 individuals diagnosed with HCM. Two of the individuals carried another variant in the MYBPC3 gene in a compound heterozygous state with the p.Arg502Trp variant, and another 11 carried an additional variant in either MYBPC3 or another sarcomere gene (Richard et al. 2003; Van Driest et al. 2004; Ingles et al. 2005; Maron et al. 2008; Marston et al. 2009; Saltzman et al. 2010; Kaski et al. 2012; Lopes et al. 2013; Camuglia et al. 2013). The Arg502Trp variant has also been reported in a heterozygous state in three individuals diagnosed with left ventricular noncompaction cardiomyopathy. One of the individuals was the son of a female proband with HCM who also carried the variant in a heterozygous state. The two other individuals were the brother and nephew of another proband with HCM who also carried the variant in a heterozygous state (Camuglia et al. 2013). The p.Arg502Trp variant was absent from 945 controls (Van Driest et al. 2004; Saltzman et al. 2010) and is reported at a frequency of 0.0001026 in the European (non-Finnish) population of the Genome Aggregation Database. The variant has been shown to segregate with disease in multiple families (Saltzman et al. 2010). Based on the collective evidence, the p.Arg502Trp variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000252398 SCV000696313 pathogenic Cardiovascular phenotype 2016-07-26 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.1504C>T (p.Arg502Trp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/122664 control chromosomes at a frequency of 0.0000245, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in numerous HCM patients, with evidence of co-segregation of variant with disease in some of the families. Structure study predicted the R502W mutation and other HCM-linked mutations found within the same C3 domain, may directly disrupt the interaction of cMyBP-C with other sarcomeric proteins (Zhang_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. It is the most common pathogenic HCM variant identified by our laboratory. Taken together, this variant is classified as pathogenic.
Invitae RCV000203913 SCV000260968 pathogenic Hypertrophic cardiomyopathy 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 502 of the MYBPC3 protein (p.Arg502Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs375882485, ExAC 0.01%). This variant has been shown to segregate with hypertrophic cardiomyopathy in more than ten families in the literature, and has been observed in many unrelated hypertrophic cardiomyopathy patients across multiple studies (PMID: 12707239, 20378854, 22267749, 23396983). ClinVar contains an entry for this variant (Variation ID: 42540). A different missense substitution at this codon (p.Arg502Gln) has been reported to segregate with disease in families affected with hypertrophic cardiomyopathy (PMID: 9562578, 22386539). This indicates that the Arg502 residue is important for MYBPC3 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000203913 SCV000059054 pathogenic Hypertrophic cardiomyopathy 2011-06-16 criteria provided, single submitter clinical testing The p.Arg502Trp variant in MYBPC3 has been well reported in many individuals acr oss multiple studies and is known to be pathogenic for hypertrophic cardiomyopat hy (HCM). It is also the most common pathogenic HCM variant identified by our la boratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based upon multiple reports in affected individuals and extensive segregation studies (Richard 2003, Van Driest 2004, Carballo 2005, Ingles 2005, Maron 2008, Kaski 2009, Marston 2009, Saltzman 2010). ACMG/AMP cri teria applied: PS4, PP1_Strong.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223898 SCV000280214 pathogenic not provided 2014-07-08 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.Arg502Trp This variant has been reported in at least 37 cases of HCM, with strong segregation data. Richard et al (2003) reported this variant in one individual with HCM in their French cohort. Van Driest et al (2004) observed this variant in an HCM patient who also carried p.Gly5Arg in MYBPC3. Details regarding phase and the severity of phenotype were not reported for this patient However, a comparison of the 10 patients, including this one, with multiple variants to the patients with a single variant revealed that the multiple variant group had, on average, a more severe phenotype. Ingles et al (2005) reported observing this variant in one case of HCM. Saltzman et al (2010) reported p.Arg502Trp in 34 of 1414 (2.4%) unrelated cases of HCM, making it the most common variant in that cohort. Four families had another sarcomere variant and individuals with multiple variants were more likely to have severe clinical outcomes. They noted that ~50% of carriers of p.Arg502Trp had overt disease by age 45. They reported a combined Lod score of 4.04 and noted that the likelihood that the observed cosegregation happened by chance was 1/11,000. The highest number of family members cosegregating HCM and the variant in one individual family was three. Note that this paper includes a pedigree reported online by the Seidman group (pedigree FU). Morita et al (2008) observed the variant in two unrelated children with HCM. In one of those cases and affected parent also had the variant. One of these children also carried p.Ser858Asn in MYBPC3 (phase not reported) Note that these families may have been included in the subsequent report by Saltzman et al. Liu et al (2006) reported a Chinese patient with HCM who carried both p.Arg502Trp and IVS27+12C>T, also in MYBPC3. The arginine at codon 502 is highly conserved across species. This mutation results in a non-conservative amino acid change of a positively charged Arginine residue with a non-polar Tryptophan. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Another variant at the same codon has been reported in association with HCM (p.Arg502Gln, which we consider very likely disease causing), as have variants in nearby codons (p.Arg495Gln, p.Lys505del, p.Gly507Arg). In total the variant has not been seen in ~395 published controls, including 100 (Richard et al 2003), 200 (van Driest et al 2004), 95 (Saltzman et al 2010). The variant was observed in 1 of 3472 Caucasians and 0 of 1826 African Americans in the NHLBI Exome Sequence Project dataset (as of 7/8/2014). Individual phenotypes from that dataset are not available. Several different cohorts from studies on common complex cardiovascular disease were pooled to create that sample. There is no variant at codon 502 listed in dbSNP or 1000 genomes (as of 7/8/2014).

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.