ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000589860 SCV000739944 pathogenic Cardiovascular phenotype 2017-04-21 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,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171824 SCV000054769 pathogenic Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Blueprint Genetics RCV000171824 SCV000264026 pathogenic Primary familial hypertrophic cardiomyopathy 2015-03-18 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000168090 SCV000492795 likely pathogenic Hypertrophic cardiomyopathy 2015-09-07 criteria provided, single submitter clinical testing
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
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.
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.
Integrated Genetics/Laboratory Corporation of America RCV000589860 SCV000696312 pathogenic Cardiovascular phenotype 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.1484G>A (p.Arg495Gln) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/124622 control chromosomes at a frequency of 0.000008, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). Variant of interest has been reported in more than 20 HCM patients in the literature. In one family, this variant co-segregates with HCM in three affected family members, however, one unaffected family member whose age was above the age of onset carried this variant implying on 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). Multiple clinical laboratories classified this variant as likely pathogenic/pathogenic without evidence to independently evaluate. Taken together, this variant was classified as Pathogenic.
Invitae RCV000168090 SCV000218744 pathogenic Hypertrophic cardiomyopathy 2018-12-27 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 for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168090 SCV000198912 likely pathogenic Hypertrophic cardiomyopathy 2016-08-11 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 199 8, Maron 2001, Van Driest 2004, Ehlermann 2008, Fokstuen 2008, Morita 2008, Mill at 2010, Fokstuen 2011, Brito 2012 personal communication, Lopes 2013, Marsiglia 2013, Kapplinger 2014, LMM data). However, multiple unaffected relatives from d ifferent families also carried this variant, at least 6 of whom were over the ag e of 50 (Brito 2012, LMM data), suggesting reduced penetrance. This variant has also been identified in 4/111680 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200411226). In vitro functional studies suggest that carriers exhibit heightened expression of MYBPC 3 as compared to controls, leading to an abundance of the mutant protein in card iac tissue (Helms 2014). However, it is unclear how this would impact cardiac fu nction. In addition, two different variants at the same position (p.Arg495Gly an d p.Arg495Trp) have been identified in individuals with HCM, suggesting that a c hange at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though t his information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical signif icance, the p.Arg495Gln variant is likely 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
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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