NM_000256.3:c.1513_1515delAAG
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM4_SupportingPP5_Very_Strong
The NM_000256.3(MYBPC3):c.1513_1515delAAG(p.Lys505del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000991 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000256.3 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1513_1515delAAG | p.Lys505del | conservative_inframe_deletion | Exon 17 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.1513_1515delAAG | p.Lys505del | conservative_inframe_deletion | Exon 16 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.1513_1515delAAG | non_coding_transcript_exon_variant | Exon 17 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249264Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135220
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461698Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727134
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74382
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:4
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This variant causes an in-frame deletion of one amino acid at codon 505 in the Ig-like domain C3 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 16566405, 20433692, 24093860, 27532257, 28138913, 28771489, 31006259, 32268277, 32841044; Sabater-Molina et al 2013). It has been shown that this variant segregates with disease in three families (PMID: 20433692, 28771489; communication with an external laboratory, ClinVar SCV000203959.5). This variant has also been reported in one individual affected with left ventricular non-compaction (PMID: 24602869); in three individuals affected with dilated cardiomyopathy (PMID: 30847666, 32826072, 37904629); and in two individuals affected with sudden cardiac death (PMID: 28255936, 33336002), one of whom also carried a pathogenic truncation variant in the same gene (PMID: 33336002). This variant has been identified in 3/280658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
This variant, c.1513_1515del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Lys505del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs727504287, gnomAD 0.003%). This variant has been observed in individuals with clinical features of MYBPC3-related conditions (PMID: 12707239, 16566405, 20433692, 24093860, 24602869, 27532257, 28138913, 28255936, 30847666; internal data). This variant is also known as Del [10957-10959] (Del K504). ClinVar contains an entry for this variant (Variation ID: 177699). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
The p.Lys505del variant in MYBPC3 has been reported in at least 15 heterozygous individuals with HCM, 1 individual with SCD, 2 individuals with DCM and 1 infant with severe early-onset left ventricular noncompaction, who carried a second pathogenic variant in MYBPC3. Additionally, it segregated with disease in 3 affected individuals from 3 families (Cardim 2005 PMID: 16566405, Mademont-Soler 2017 PMID: 28771489, Marsiglia 2013 PMID: 24093860, Richard 2003 PMID: 12707239 , Rodriguez-Garcia 2010 PMID: 20433692, Schaefer 2014 PMID: 24602869, Sabater-Molina 2013 DOI:10.4081/cardiogenetics.2013.e5, Campuzano 2017 PMID: 28255936, Norrish 2019 PMID: 31006259, van Lint 2019 PMID: 30847666, Ambry pers. comm., Invitae pers. comm., Bristol Genetics Laboratory pers. comm., LMM data). It has also been identified in 1/35360 Latino chromosomes and 2/128444 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org). This variant is a deletion of 1 amino acid at position 505 and is not predicted to alter the protein reading-frame; it is unclear if this deletion will impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Strong, PM2_Supporting, PM4_Supporting, PP1. -
not provided Pathogenic:1Uncertain:2
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PM2_supporting, PM4, PS4 -
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Cardiomyopathy Pathogenic:2
The c.1513_1515del variant in MYBPC3 is predicted to cause an in-frame deletion of 1 amino acid at codon 505. It has also been previously reported as p.Lys504del using alternate nomenclature. It has a Grpmax Filtering Allele Frequency of 0.0003% in control populations in the Genome Aggregation Database (gnomAD). It has been previously reported in at least 15 apparently unrelated individuals with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular non-compaction cardiomyopathy (LVNC) (PMID 12707239, 16566405, 20433692, 24093860, 24602869, 27532257, 32268277, 34400558, 32826072, 31006259, 30847666 and others; ClinVar database, CHEO internal data). It was reported in a compound heterozygous state in an infant with a severe form of LVNC who carried a secondary pathogenic variant in MYBPC3 (p.Pro955fs); the p.Lys505del variant was inherited from an unaffected mother, while the p.Pro955fs variant was inherited from a father with HCM (PMID 24602869). This variant has also been reported in a compound heterozygous state in two other individuals: a postmortem case of cardiac death with suspected LVNC in which the proband also carried a pathogenic MYBPC3 variant (p.Pro955Argfs*95) (PMID 33336002), and in a patient with HCM who also carried a pathogenic TNNT2 variant (p.W287*) (PMID 28771489). This variant was reported to segregate with disease in at least 3 families (PMID 20433692, ClinVar database). In silico prediction programs predict that this variant is unlikely to affect splicing. However, this prediction has not been confirmed by RNA functional studies. This variant is listed in ClinVar (VCV000177699). Based on the above information, we categorize this variant as likely pathogenic. -
This variant causes an in-frame deletion of one amino acid at codon 505 of the MYBPC3 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 16566405, 20433692, 24093860, 27532257, 28138913, 28771489, 31006259, 32268277; Sabater-Molina et al 2013). It has been shown that this variant segregates with disease in three families (PMID: 20433692, 28771489; communication with an external laboratory). This variant has also been reported in an individual affected with left ventricular non-compaction (PMID: 24602869), in individuals affected with dilated cardiomyopathy (PMID: 30847666, 32826072), and in an individual affected with sudden cardiac death (PMID: 28255936). This variant has been identified in 3/280658 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Hypertrophic cardiomyopathy 4 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The c.1513_1515delAAG variant (also known as p.K505del) is located in coding exon 17 of the MYBPC3 gene. This variant results from an in-frame AAG deletion at nucleotide positions 1513 to 1515. This results in the in-frame deletion of a lysine at codon 505. This variant was reported in individuals with features consistent with hypertrophic cardiomyopathy (HCM) (Richard P et al. Circulation, 2003 May;107:2227-32; Cardim N et al. Rev Port Cardiol, 2005 Dec;24:1463-76; Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Schaefer E et al. Eur J Med Genet, 2014 Mar;57:129-32; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Campuzano O et al. Sports Med, 2017 Oct;47:2101-2115; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Field E et al. J Med Genet, 2022 Aug;59:768-775). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Ambry internal data). This amino acid position is highly 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hypertrophic cardiomyopathy 1 Pathogenic:1
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MYBPC3-related disorder Pathogenic:1
ACMG classification criteria: PS4, PM2, PM4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at