rs727504288

Positions:

• chr11-47337549-CTCT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM4_Supporting PP5

The NM_000256.3(MYBPC3):​c.2441_2443delAGA​(p.Lys814del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000372 in 1,613,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K814K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:12
• Conservation: PhyloP100: 4.70

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Fibronectin type-III 1 (size 96) in uniprot entity MYPC3_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000256.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000256.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-47337549-CTCT-C is Pathogenic according to our data. Variant chr11-47337549-CTCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177700.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=12, Likely_pathogenic=4}. Variant chr11-47337549-CTCT-C is described in Lovd as [Pathogenic]. Variant chr11-47337549-CTCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2441_2443delAGA	p.Lys814del	disruptive_inframe_deletion	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2441_2443delAGA	p.Lys814del	disruptive_inframe_deletion	25/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2441_2443delAGA	p.Lys814del	disruptive_inframe_deletion	24/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2414-41_2414-39delAGA		intron_variant		5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461198 Hom.: 0 AF XY: 0.0000440 AC XY: 32 AN XY: 726856

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152162 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:4 Uncertain:2

Likely pathogenic, flagged submission	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Dec 30, 2024	The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.004%). The variant is epected to result in an in-frame deletion in the non-repeat region can change the length of the protein and disrupt protein function. In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. The variant has been observed in at least 17 similarly affected unrelated individuals (3billion dataset). Therefore, variant is classified as likely pathogenic based on ACMG guidelines. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM4+PS4_Moderate+PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 20 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated fibronectin 3 domain (NCBI). (I) 0705 - No comparable in-frame deletion variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has been reported as likely pathogenic and VUS in multiple individuals with HCM (ClinVar, DECIPHER, cardiodb, VCGS, PMIDs: 31513939, 32492895). It has also been reported as likely pathogenic in a DCM patient (PMID: 26084686). (I) 1010 - Functional evidence for this variant is inconclusive. Functional studies showed the level of protein in COS-7 cells with this variant was similar to wild-type (PMID: 18929575). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	clinical testing	Cardiology unit, Meyer University Hospital	Sep 27, 2022	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 14, 2019	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. -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	MYBPC3: PM1, PM2, PM4:Supporting, BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 09, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2024	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) -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	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. -
Likely pathogenic, flagged submission	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 30, 2023	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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 27, 2023

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. -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 11, 2015

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504288; hg19: chr11-47359100;