ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1831G>A (p.Glu611Lys) (rs730880555)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244596 SCV000317936 uncertain significance Cardiovascular phenotype 2019-05-10 criteria provided, single submitter clinical testing The p.E611K variant (also known as c.1831G>A), located in coding exon 19 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1831. The glutamic acid at codon 611 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple hypertrophic cardiomyopathy cohorts, a dilated cardiomyopathy cohort, and a noncompaction cardiomyopathy cohort; however, clinical details were limited and at least one patient was also heterozygous for a pathogenic MYBPC3 alteration (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67; Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000244596 SCV000696320 likely pathogenic Cardiovascular phenotype 2016-08-02 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.1831G>A (p.Glu611Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is located in the Immunoglobulin I domain (InterPro). Other missense variants around this region have also been reported in HCM patients, such as p.Tyr614Cys, p.Asp610Val, p.Asp610His, p.Asp610Asn, p.Ala609Val, etc., suggesting a notion that the region is important for protein function; however they have conflicting interpretations of pathogenicity ranging from pathogenic to uncertain significance in ClinVar. This variant is absent in 52198 control chromosomes but has been reported in at least nine patients (2 DCM, 7 HCM) from multiple countries. However, there are no co-segregation studies in literature, nor are functional studies. One DCM patient was not comprehensively genotyped (Waldmuller_2014) while another DCM patient also has unspecified mutation(s) (Wang_2014). Thus, it may be possible that it is HCM-specific mutation. This variant was also found in one HCM patient who also carried another frameshift mutation in the same gene; however, phenotypic severity of the patient is not specified. One clinical lab has classified it as pathogenic. Taken together, this variant is classified as Probable Disease Variant (or Likely Pathogenic).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000615268 SCV000731277 uncertain significance not specified 2019-02-07 criteria provided, single submitter clinical testing The p.Glu611Lys variant in MYBPC3 has been reported in 2 individuals with HCM (Miller 2013, Zou 2013), in 1 individual with DCM (Waldmuller 2011) and in 1 individual with non compaction cardiomyopathy (Waning 2018). Of note, one of these individuals with HCM also carried a pathogenic variant in MYBPC3 (Miller 2013). It is present in CLinVar (ID 180955) (conflicting interpretations). The p.Glu611Lys variant was also identified in 1/27268 of South Asian chromosomes in gnomAD. Computational prediction tools and conservation analysis suggest that the p.Glu611Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu611Lys variant is uncertain.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000600155 SCV000743558 likely pathogenic Familial hypertrophic cardiomyopathy 4 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000600155 SCV000744847 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Invitae RCV000695616 SCV000824127 uncertain significance Hypertrophic cardiomyopathy 2020-09-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 611 of the MYBPC3 protein (p.Glu611Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy, dilated cardiomyopathy, or noncompaction cardiomyopathy (PMID: 23283745, 21750094, 24111713, 23054336, 29447731, 31513939). ClinVar contains an entry for this variant (Variation ID: 180955). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Center for Human Genetics,University of Leuven RCV000695616 SCV000886822 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769326 SCV000900704 uncertain significance Cardiomyopathy 2019-01-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000769326 SCV001357701 uncertain significance Cardiomyopathy 2018-11-29 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000600155 SCV000733045 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV001706060 SCV001921022 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001706060 SCV001930797 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001706060 SCV001953624 pathogenic not provided no assertion criteria provided clinical testing

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