ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3413G>A (p.Arg1138His) (rs187705120)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000154288 SCV000208170 uncertain significance not specified 2014-07-17 criteria provided, single submitter clinical testing p.Arg1138His (CGC>CAC): c.3413 G>A in exon 31 of the MYBPC3 gene (NM_000256.3). The R1138H variant has been reported previously as a benign change and in association with cardiac disease (Jaaskelainen et al., 2002; Garcia-Castro et al., 2009; Golbus et al., 2012). Jaaskelainen et al. (2002), reported that R1138H as a likely benign polymorphism in the Finnish population due to the presence of R1138H in 5 of 111 healthy control individuals, including unaffected homozygous carriers of this variant, and R1138H did not co-segregate with the HCM phenotype in two families. However, Garcia-Castro M et al. (2009) reported R1138H to be a disease-causing mutation in a 60 year old male patient with dyspnea, atrial fibrillation, and angina with no family history. Furthermore, Golbus et al. (2012) queried 1092 individuals in the 1000 Genomes database for three sarcomeric genes, and identified one individual with the R1138H variant, who also harbored a variant in the MYH7 gene. The R1138H variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense mutations in nearby residues (I1131T, N1133D) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (CirinoAet al., 2011; Hershberger R et al., 2009). The variant is found in HCM,DCM-CRDM panel(s).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000172893 SCV000223884 likely benign Familial hypertrophic cardiomyopathy 1 2015-03-18 criteria provided, single submitter research The MYBPC3 Arg1138His variant has been previously reported in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.017 (72 of 4168 in the European Finnish population), and at a frequency of 0.002 in the European sub-population of the 1000 genomes project (http://www.1000genomes.org/). We observed this variant in a single proband with typical HCM, presented 27 years and has no clear family history of disease. No other variants were identified. The variant has been reported in the literature (Jääskeläinen P, et al., 2002; García-Castro M, et al., 2009; Golbus JR, et al., 2012). Jääskeläinen et al. (2002) sequenced MYBPC3 in a Finnish HCM population and normal cohort, and identified this Arg1138His variant in multiple families (3 unrelated probands and 5 normal control samples). The variant does not co-segregate with disease and homozygous individuals did not express the HCM phenotype. Another report from Garcia-Castro et al. (2009) identified the Arg1138His variant in a single proband amongst a Spanish HCM population, however this proband is described as having no family history of disease and a concentric pattern of hypertrophy (IVS and PW 19mm). Arginine (Arg) at position 1138 is conserved across distantly related species, however the computational tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), cannot predict the outcome of this MYBPC3 Arg1138His variant. Due to the allele frequency of > 0.001 in population databases, and literature evidence, we classify this variant as "likely benign".
Invitae RCV000629118 SCV000750032 benign Hypertrophic cardiomyopathy 2017-09-13 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845563 SCV000987692 likely benign not provided criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852647 SCV000995352 likely benign Cardiomyopathy 2017-12-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154288 SCV000203947 uncertain significance not specified 2013-02-11 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics RCV000157320 SCV000207055 likely benign Primary familial hypertrophic cardiomyopathy 2014-03-25 no assertion criteria provided clinical testing
Blueprint Genetics RCV000157321 SCV000207056 likely benign Primary dilated cardiomyopathy 2014-03-25 no assertion criteria provided clinical testing

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