chr11-47337549-CTCT-C
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PM4_Supporting
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
Consequence
NM_000256.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 4Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompaction 10Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.2441_2443delAGA | p.Lys814del | disruptive_inframe_deletion | Exon 25 of 35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.2441_2443delAGA | p.Lys814del | disruptive_inframe_deletion | Exon 25 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.2441_2443delAGA | p.Lys814del | disruptive_inframe_deletion | Exon 24 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.2414-41_2414-39delAGA | intron_variant | Intron 24 of 26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152162Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000644 AC: 16AN: 248588 AF XY: 0.0000667 show subpopulations
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461198Hom.: 0 AF XY: 0.0000440 AC XY: 32AN XY: 726856 show subpopulations
Age Distribution
GnomAD4 genome 0.0000263 AC: 4AN: 152162Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74324 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Pathogenic:3Uncertain:3
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)
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
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.
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in at least two similarly affected unrelated individuals (3billion dataset). The variant has been reported to be associated with MYBPC3 related disorder (PMID: 12110947 /3billion dataset). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
not provided Uncertain:4
MYBPC3: PM1, PM2, PM4:Supporting, BS3:Supporting
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.
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:1Uncertain:1
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, 30105547, 31513939, 31737537, 33297573, 33407484, 35208637). This variant is also known as K811del. Algorithms developed to predict the effect of variants on gene product 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.
Cardiovascular phenotype Pathogenic:1Uncertain:1
PS4, PM2, PM4
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 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; Field E et al. J Med Genet. 2022 Aug;59(8):768-775; Ambry internal data). 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.
Cardiomyopathy Uncertain:2
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
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
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at