ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244596 SCV000317936 uncertain significance Cardiovascular phenotype 2012-11-15 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,Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America 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 2016-11-17 criteria provided, single submitter clinical testing The p.Glu611Lys variant in MYBPC3 has been reported in 2 individuals with HCM (M iller 2013, Zou 2013) and in 1 individual with DCM (Waldmuller 2011). Of note, o ne of these individuals with HCM also carried a pathogenic variant in MYBPC3 (Mi ller 2013). The p.Glu611Lys variant was absent from large population studies. Co mputational prediction tools and conservation analysis suggest that the p.Glu611 Lys variant may impact the protein, though this information is not predictive en ough 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
DNA and Cytogenetics Diagnostics Unit,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 2018-07-30 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 or dilated cardiomyopathy (PMID: 23283745, 21750094, 24111713, 23054336). 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 2017-10-04 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

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