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

dbSNP: rs727504288

Total submissions: 15

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	2024-06-23	criteria provided, single submitter	clinical testing	Reported multiple times in association with HCM and in at least one patient with DCM (PMID: 12110947, 15114369, 15519027, 15563892, 16566405, 16715312, 18957093, 18929575, 21499742, 23054336, 24093860, 23674513, 24111713, 26084686, 33148509, 25499402, 31513939, 31737537, 32492895, 33297573); 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 (PMID: 18929575), however, any other aspects of cardiac myosin-binding protein C function were not assessed; In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a non-repeat region; Also known as Lys811del, Lys812del, or Lys813del, due to alternative nomenclature; This variant is associated with the following publications: (PMID: 16715312, 16566405, 21415409, 15563892, 21499742, 23054336, 12110947, 20800588, 20474083, 15114369, 25524337, 26688388, 15519027, 18957093, 24111713, 28518168, 26084686, 24093860, 23674513, 35653365, 34400558, 35208637, 28771489, 30105547, AlloubaM2022[Preprint], 36588553, 33407484, 33057194, 36252119, 37652022, 24721642, 32380161, 35352813, 35982159, 18929575, 33148509, 25499402, 31513939, 31737537, 32492895, 33297573)
Labcorp Genetics (formerly Invitae), Labcorp	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004562309	SCV000696322	uncertain significance	not specified	2023-11-27	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2441_2443delAGA (p.Lys814del) results in an in-frame deletion that is predicted to remove one amino acid from the fibronectin type III domain (IPR003961) of the encoded protein. The variant allele was found at a frequency of 3.7e-05 in 1614122 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (3.7e-05 vs 0.001), allowing no conclusion about variant significance. c.2441_2443delAGA has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy without strong evidence for causality, and has been reported in several unaffected relatives (e.g. Jaaskelainen_2002, Micheu_2019). This variant has also been reported in one individual with Dilated Cardiomyopathy (Akinrinade_2015) and in a cohort of individuals with unspecified Cardiomyopathies (Stava_2023). These reports do not allow any conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on mRNA or protein expression, or 20S proteasome activity in vitro (Bahrudin_2008). The following publications have been ascertained in the context of this evaluation (PMID: 26084686, 15114369, 18929575, 24111713, 16566405, 32380161, 18957093, 34400558, 24888384, 12110947, 24093860, 23054336, 31513939, 15563892, 35653365, 15519027, 23674513, 16715312, DOI: 10.25083/rbl/24.1/91.99). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Ten submitters classified the variant as uncertain significance and two classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as 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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000587228	SCV005197508	uncertain significance	not provided	2022-05-27	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)