ClinVar Miner

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

dbSNP: rs727504288
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000587228 SCV000203960 uncertain significance not provided 2023-01-09 criteria provided, single submitter clinical testing The p.Lys814del variant in MYBPC3 has been identified in at least 20 individuals with HCM and segregated with disease in 2 affected relatives from 2 families. It has also been identified in 1 individual with DCM (Jääskeläinen 2002 PMID: 12110947, Van Driest 2004 PMID: 15519027, Andersen 2004 PMID: 15114369, Cardim 2005 PMID: 16566405, Song 2005 PMID: 15563892, Zeller 2006 PMID: 16715312, Bahrudin 2008 PMID: 18929575, Ehlermann 2008 PMID: 18957093, Marsiglia 2013 PMID: 24093860, Berge 2014 PMID: 24111713, Akinrinade 2015 PMID: 26084686, Rupp 2019 PMID: 30105547, Marschall 2019 PMID: 31737537, Micheu 2020 PMID: 33297573, Robyns 2020 PMID: 31513939, Kim 2020 PMID: 32492895, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID #177700) and has been identified in 0.016% (4/24882) of Finnish chromosomes by gnomAD (https://gnomad.broadinstitute.org, v.3.1.2) and. This variant is a deletion of 1 lysine (Lys) residue at position 814 from a stretch of 4 lysines. It is unclear if this deletion will impact protein function. An in vitro study did not demonstrate an impact on protein function (Bahurdin 2008 PMID: 18929575). In summary, the clinical significance of the p.Lys814del variant is uncertain. ACMG/AMP Criteria applied: PS4_supporting, BS3_Supporting.
Blueprint Genetics RCV000157327 SCV000207063 uncertain significance Primary familial hypertrophic cardiomyopathy 2015-02-11 criteria provided, single submitter clinical testing
GeneDx RCV000587228 SCV000208298 uncertain significance not provided 2021-04-05 criteria provided, single submitter clinical testing An in vitro functional study of this variant showed normal protein levels when expressed in COS-7 cells, and the variant did not destabilize the protein through the ubiquitin-proteasome system as was shown for another MYBPC3 variant (Bahrudin et al., 2008), however, any other aspects of cardiac myosin-binding protein C function were not assessed; Reported in ClinVar as a variant of uncertain significance by several laboratories (ClinVar Variant ID# 177700; Landrum et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16715312, 16566405, 21415409, 15563892, 21499742, 23054336, 12110947, 33297573, 20800588, 20474083, 18929575, 15114369, 25524337, 26688388, 15519027, 18957093, 24111713, 28518168, 26084686, 24093860, 23674513, 31513939, 31737537, 32492895, 33148509)
Invitae RCV000196806 SCV000254435 uncertain significance Hypertrophic cardiomyopathy 2023-12-20 criteria provided, single submitter clinical testing This variant, c.2441_2443del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Lys814del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with MYBPC3-related conditions (PMID: 12110947, 15519027, 15563892, 16566405, 16715312, 18929575, 18957093, 23674513, 24093860, 24111713, 26084686, 31513939, 31737537, 33297573, 33407484, 35208637). This variant is also known as K811del. ClinVar contains an entry for this variant (Variation ID: 177700). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant does not substantially affect MYBPC3 function (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.
Color Diagnostics, LLC DBA Color Health RCV000777726 SCV000913673 uncertain significance Cardiomyopathy 2023-03-30 criteria provided, single submitter clinical testing This variant causes a deletion of one lysine residue from 4 consecutive lysine residues present in codons 811-814 of the MYBPC3 protein. A functional 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, 33297573), left atrial enlargement (PMID: 33407484), dilated cardiomyopathy (PMID: 26084686), or sudden death (PMID: 26688388, 36588553). This variant has been identified in 17/279948 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV000587228 SCV001249481 uncertain significance not provided 2022-09-01 criteria provided, single submitter clinical testing MYBPC3: PM1, PM2, PM4:Supporting, BS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000168801 SCV001367745 uncertain significance Hypertrophic cardiomyopathy 4 2019-02-14 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM4.
3billion RCV000168801 SCV002058346 uncertain significance Hypertrophic cardiomyopathy 4 2022-01-03 criteria provided, single submitter clinical testing This inframe deletion in the non-repeat region can change the length of the protein and disrupt protein function (PM4_M).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000177700, PMID:12110947). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000061, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Ambry Genetics RCV002453508 SCV002737954 uncertain significance Cardiovascular phenotype 2023-12-04 criteria provided, single submitter clinical testing The c.2441_2443delAGA variant (also known as p.K814del) is located in coding exon 25 of the MYBPC3 gene. This variant results from an in-frame AGA deletion at nucleotide positions 2441 to 2443. This results in the in-frame deletion of a lysine at codon 814, removing one of the lysines in a four-lysine tract. This variant has been reported in individuals with pediatric onset hypertrophic cardiomyopathy (Maron BJ et al. Am J Cardiol, 2015 Feb;115:402-4; Rupp S et al. Clin Res Cardiol, 2019 Mar;108:282-289). This alteration (also reported as p.K811del) has been detected in a number of hypertrophic cardiomyopathy cohorts as well as a dilated cardiomyopathy cohort, but clinical details were frequently limited and some of the probands also had alterations in other cardiac-related genes (e.g., Van Driest SL et al. J. Am. Coll. Cardiol. 2004;44:1903-10; Cardim N et al. Rev Port Cardiol. 2005;24:1463-76; Song L et al. Clin. Chim. Acta. 2005;351:209-16; Zeller R et al. J. Mol. Med. 2006;84:682-91; Ehlermann P et al. BMC Med. Genet. 2008;9:95; Miller EM et al. J Genet Couns. 2013;22:258-67; Berge KE et al. Clin. Genet. 2014;86:355-60; Jääskeläinen P et al. Ann. Med. 2014;46:424-9; Akinrinade O et al. Eur. Heart J. 2015;36:2327-37; Mademont-Soler I et al. PLoS ONE. 2017;12:e0181465). In one study, this alteration did not affect MYBPC3 protein stability; however, protein function was not tested (Bahrudin U et al. J. Mol. Biol. 2008;384:896-907). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al., PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000777726 SCV003838942 uncertain significance Cardiomyopathy 2021-06-01 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000168801 SCV000256176 likely pathogenic Hypertrophic cardiomyopathy 4 flagged submission clinical testing
Center for Human Genetics, University of Leuven RCV000196806 SCV000886760 likely pathogenic Hypertrophic cardiomyopathy 2018-10-31 flagged submission clinical testing
Cardiology unit, Meyer University Hospital RCV000168801 SCV002577348 likely pathogenic Hypertrophic cardiomyopathy 4 2022-09-27 no assertion criteria provided clinical testing The c.2441_2443del in MYBPC3 is an inframe deletion that has been reported in multiple patients with Hypertrophic Cardiomyopathy (Jaaskelainen et al J Mol Med (Berl) 2002; Kim et al J Clin Med 2020; Bagnall et al Circ Genom Precis Med 2022; Field et al J Med Genet 2022). The variant has been reported in GnomAD with an extremely low frequency (MAF 0.006%) but metrics indicate poor data quality. It is located in a well established functional domain or exonic hotspot, where pathogenic variants have frequently reported. The c.2441_2443del co-segregates with Hypertrophic Cardiomyopathy for three meiosis (internal laboratory data). ClinVar and HGMD Professional databases contains an entry for this variation (Variation ID 177700 and CD021840). Even if one study has shown that this variant does not substantially affect MYBPC3 stability (Bahrudin U et al J Mol Biol 2008), these results are insufficient to demonstrated the normal function of the protein. In conclusion, according to the recommendation of ACMG/AMP guideline, the c.2441_2443del is classified as likely pathogenic (PM4_M; PM1_M; PM2_S; PP1_S)

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