ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2432_2434AGA[3] (p.Lys814del) (rs727504288)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000157327 SCV000207063 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-02-11 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000587228 SCV000927956 uncertain significance not provided 2018-09-27 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000196806 SCV000886760 likely pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000777726 SCV000913673 uncertain significance Cardiomyopathy 2018-10-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is located in the fibronectin type 3 domain C6 of the MYBPC3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An an experimental study has shown that this variant does not have adverse effects on protein expression levels or stability (PMID: 18929575). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 18929575, 23674513, 23711808, 24111713), dilated cardiomyopathy (PMID: 26084686) and sudden death (PMID: 26688388). This variant has also been identified in 17/276520 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000154301 SCV000208298 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing The c.2441_2443delAGA variant of uncertain significance (also reported as Lys811del, Lys812del, or Lys813del due to alternative nomenclature) in the MYBPC3 gene has been reported multiple times in association with HCM (Andersen et al., 2004; van Driest et al., 2004; Song et al., 2005; Cardim et al., 2005; Zeller et al., 2006; Ehlermann et al., 2008; Bahrudin et al., 2008; Allegue et al., 2011). The c.2441_2443delAGA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.2441_2443delAGA variant results in the deletion of the lysine residue at position 814 of the cardiac myosin-binding protein C and does not result in a shift in reading frame. Additionally, functional studies show the level of protein in COS-7 cells with the c.2441_2443delAGA variant was similar to the wild type (Bahrudin et al., 2008).
Integrated Genetics/Laboratory Corporation of America RCV000587228 SCV000696322 uncertain significance not provided 2016-08-29 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.2441_2443delAGA (p.Lys814del) variant involves the alteration of a conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. This variant was found in 39/121304 control chromosomes at a frequency of 0.0003215, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM patients and two unaffected relatives. This variant has also been reported in one DCM patient (Akinrinade_2015). One in vitro study showed that this variant did not affect mRNA or protein expression of MYBPC3, or 20S proteasome activity (Bahrudin_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance or likely pathogenic. Taken together, this variant is classified as VUS until additional information is available.
Invitae RCV000196806 SCV000254435 uncertain significance Hypertrophic cardiomyopathy 2018-09-19 criteria provided, single submitter clinical testing This variant, c.2441_2443delAGA, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Lys814del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs727504288, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy and in an individual affected with dilated cardiomyopathy (PMID: 12110947, 15519027, 15563892, 16566405, 18957093, 16715312, 18929575, 23674513, 24111713, 26084686, 24093860). This variant is also known as K811del in the literature. ClinVar contains an entry for this variant (Variation ID: 177700). Experimental studies have shown that this deletion does not lead to decreased MYBPC3 stability in vitro; however, the clinical significance of this observation is uncertain (PMID: 18929575). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154301 SCV000203960 uncertain significance not specified 2015-04-28 criteria provided, single submitter clinical testing The p.Lys814del variant in MYBPC3 has been reported in 7 individuals with HCM (J aaskelainen 2002, Van Driest 2004, Andersen 2004, Cardim 2005, Song 2005, Bahrud in 2008, Ehlermann 2008) and has been identified by our laboratory in 3 individu als with HCM (2 adults and 1 infant). It has also been identified in 4 unaffecte d adult relatives from 2 families (Jaaskelainen 2002, LMM unpublished data). In addition, the p.Lys814del variant has been identified in 25/66666 European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ). This variant is a deletion of 1 lysine (Lys) residue at position 814 from a s tretch of lysines. It is unclear if this deletion will impact protein function. In summary, the clinical significance of the p.Lys814del variant is uncertain.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000168801 SCV000256176 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing

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