ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.13G>C (p.Gly5Arg) (rs201278114)

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Total submissions: 10
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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 RCV000474218 SCV000054780 uncertain significance Hypertrophic cardiomyopathy 2018-04-05 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151176 SCV000198995 likely benign not specified 2018-05-18 criteria provided, single submitter clinical testing The p.Gly5Arg variant in MYBPC3 is classified as likely benign because it has be en identified in 0.06% (75/120166) of European chromosomes by the Genome Aggrega tion Database (gnomAD,; dbSNP rs201278114). Pl ease note: this variant has been reported in individuals with various cardiomyop athies (8 HCM/LVH, 2 DCM, 1 LVNC; Berge 2014, Hershberger 2010, Keeling 2010, M orita 2006, Probst 2011, Van Driest 2004, Villacorta 2014, LMM data). Due to the frequency of this variant, it would be expected, by chance, that some individua ls with cardiomyopathy may carry this variant. Furthermore, four of the individu als with HCM described above also carried pathogenic loss-of-function variants i n the MYBPC3 gene, sufficient to explain their cardiomyopathy (Berge 2014, Van D riest 2004, Villacorta 2014, LMM data). ACMG/AMP Criteria applied: BS1; BP5.
GeneDx RCV000727089 SCV000208251 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing The G5R variant of uncertain significance in the MYBPC3 gene has been published in association with HCM, DCM, and LVNC (Van Driest et al., 2004; Morita et al., 2006; Keeling et al., 2010; Hershberger et al., 2010; Probst et al., 2011; Villacorta et al., 2014). However, this variant has been reported in multiple asymptomatic relatives, and at least one individual harbored another variant in the MYBPC3 gene that is pathogenic (Van Driest et al., 2004; Morita et al., 2006; Probst et al., 2011; Villacorta et al., 2014). In a Letter to the Editor, Barriales-Villa et al. (2014) report G5A in a newborn with severe hypertrophy who also had a mutation in the GAA gene, causing Pompe disease. The G5R variant is observed in 75/120166 (0.06%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This variant 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. In addition, this variant occurs at a position where only amino acids with similar properties to glycine are tolerated across species. Nonetheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Furthermore, G5A demonstrated only weak chemical shift perturbations in experimental assays by Ratti et al. (2011). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000474218 SCV000546449 uncertain significance Hypertrophic cardiomyopathy 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 5 of the MYBPC3 protein (p.Gly5Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs201278114, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 15519027, 24111713, 24795128), dilated cardiomyopathy (DCM) (PMID: 20215591), and in an individual affected with left ventricular non-compaction (LVNC) and the unaffected mother (PMID: 21551322). However, in two of these individuals pathogenic variants were also identified in MYBPC3 (PMID: 15519027, 24795128), which suggests that this c.13G>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 161305). One experimental study has shown that this missense change does not have an effect on MYBPC3 protein function (PMID: 21297165). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727089 SCV000705558 uncertain significance not provided 2017-01-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621024 SCV000736501 uncertain significance Cardiovascular phenotype 2018-04-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000771804 SCV000904503 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ig-like domain C0 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental functional study has shown that this variant does not affect protein structure or interaction (PMID: 21297165). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 24111713, 24795128), dilated cardiomyopathy (PMID: 20215591) and left ventricular non-compaction (PMID: 21551322). In some individuals with hypertrophic cardiomyopathy, this variant co-occurred with pathogenic variants in the same gene (PMID: 15519027, 24795128). This variant occurs at an appreciable frequency in the general population and has been identified in 85/260940 chromosomes (75/120166 non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
CSER_CC_NCGL; University of Washington Medical Center RCV000148668 SCV000190392 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234987 SCV000263122 pathogenic Left ventricular hypertrophy 2015-03-28 no assertion criteria provided clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000727089 SCV000925169 uncertain significance not provided 2017-04-12 no assertion criteria provided provider interpretation Patient is a teenage Caucasian male with a recent history of palpitations and a diagnosis of LVNC on cardiac MRI, but with normal biventricular size and function. Genetic testing was done at Invitae laboratory. p.Gly5Arg (G5R; c.13G>C) in exon 1 of the MYBPC3 gene (NM_000256.3) Chromosome location 11:47374186 C / G Based on the information reviewed below, we classify this as a variant of uncertain significance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk family members. In summary, this variant has been reported in several individuals with various cardiomyopathies, yet a fair number of those individuals also carry a second pathogenic variant sufficient to explain their disease. There is only very weak published segregation data: specifically, segregating in one family member with a borderline phenotype in just one family (Villacorta et al. 2014). Furthermore, Gly5Arg is found in the population at an appreciable frequency, and changes a residue that is not well conserved across species. For those reasons, we think it is unlikely to cause disease. The Gly5Arg variant has been reported in at least 7 individuals with various forms of cardiomyopathy (5 HCM, 1 DCM, 1 LVNC). Of note: Three of the individuals with HCM also had a separate, convincingly pathogenic variant in MYBPC3. Van Driest et al. (2004) reported the variant in a proband with HCM who also had a pathogenic Arg502Trp variant in the MYBPC3 gene. Keeling et al. (2010) reported it in one individual with HCM (septal thickness 2.2 cm). Berge & Loren (2014) reported it in two Norwegian probands with HCM, one of whom also had a pathogenic truncating variant in MYBPC3 (Ser311*). Villacorta et al. from Spain reported it in a woman with HCM who also had a truncating variant in MYBPC3 in trans: Asn1023fs+28*. The truncating variant segregated with disease in the patient’s 37-year-old affected brother (septal thickness 1.9 cm, cardiac fibrosis on MRI) while Gly5Arg was not present in him. Their father, who at age 63 had borderline septal hypertrophy of 1.6 cm, a PW thickness of 1.0 cm, and a history of hypertension, had the Gly5Arg variant (which the authors interpreted as disease-causing). Their mother had the truncating variant and a normal echocardiogram. Hershberger et al. reported it in a patient with familial DCM, however no family members were available for segregation analysis. Probst et al. (2011) reported it in a proband with chest pain and left ventricular non-compaction (LVNC) as well as the patient’s 47-year-old unaffected mother. In addition, Morita et al. (2006) reported the variant in a participant in the Framingham Heart Study who had somewhat increased left ventricular wall thickness of >1.3 cm but no known diagnosis of HCM; it was also present in an elderly sibling with normal LV wall thickness. This is a non-conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a positively-charged Arginine. Glycine at this location is not well conserved across vertebrate species. It is frequently an Alanine, Valine, or Threonine instead. Arginine is, in fact, the default amino acid in at least one mammalian species. LMM reports that the change to Arginine was predicted to be benign using their computational tool clinically validated for HCM variants. This tool's benign prediction is estimated to be correct 89% of the time (Jordan 2011). Loss of function variants, such as protein-truncating variants, in the MYBPC3 gene are a well-known cause of cardiomyopathy, while certain missense variants may be tolerated. One experimental study suggests that the Gly5Arg missense change does not have an effect on MYBPC3 protein binding to myosin (Ratti et al. 2011). In total the variant has been seen in at least 85 of 131,396 published controls and individuals from publicly available population datasets. The variant was not observed in 926 published controls: 200 (100 Caucasian, 100 African American) in Van Driest et al 2004; 300 in Morita et al 2006; 246 (186 white, 23 Yoruban, 19 Asian, 18 Hispanic) in Hershberger et al 2010; 180 in Probst et al 2011. This variant was reported online in 85 individuals in the gnomAD database, which includes variant calls on 130,470 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, it was in in 75/60,083 individuals with non-Finnish European ancestry. It was also observed in 8/11,395 African and 2/15,617 Latino ancestry individuals. The overall allele frequency in gnomAD was 0.033% and the highest allele frequency was 0.062% in Europeans. For context: Whiffin et al (2016 pre-print) proposed that MYBPC3 variants with frequency greater than 0.004% are unlikely to be pathogenic for hypertrophic cardiomyopathy (HCM). The phenotype of those participants is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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