rs727504287
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM4_SupportingPP5
The NM_000256.3(MYBPC3):c.1513_1515del(p.Lys505del) variant causes a 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 inframe_deletion
NM_000256.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.89
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
?
In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 51 pathogenic changes around while only 13 benign (80%) 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 11-47342686-CCTT-C is Pathogenic according to our data. Variant chr11-47342686-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177699.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=9}. Variant chr11-47342686-CCTT-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1513_1515del | p.Lys505del | inframe_deletion | 17/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1513_1515del | p.Lys505del | inframe_deletion | 17/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1513_1515del | p.Lys505del | inframe_deletion | 16/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1513_1515del | p.Lys505del | inframe_deletion, NMD_transcript_variant | 17/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249264Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135220
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461698Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727134
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74382
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | 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; Invitae). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 27, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 24, 2021 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Dec 31, 2018 | - - |
not provided Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 19, 2023 | PM2_supporting, PM4, PS4 - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Cardiomyopathy Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 28, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 28, 2023 | 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
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | - | - - |
MYBPC3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 19, 2021 | ACMG classification criteria: PS4, PM2, PM4 - |
Hypertrophic cardiomyopathy 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Feb 20, 2020 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 12, 2017 | 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 highly conserved lysine at codon 505. This alteration was detected in an individual with a diagnosis of hypertrophic cardiomyopathy (HCM); however, gene analysis was limited (Cardim N et al. Rev Port Cardiol, 2005 Dec;24:1463-76). This alteration, has also been detected in HCM cohorts, patients referred for HCM genetic testing, and a sudden cardiac death cohort; however, clinical detail was limited (Richard P et al. Circulation, 2003 May;107:2227-32 (reported as Del K504) ; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; 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). In one study, this alteration was detected in compound heterozygosity with an MYBPC3 frameshift alteration in an infant with fatal cardiomyopathy demonstrating non-compaction, hypertrophy, and dilation. This alteration was inherited from the proband's unaffected mother, while the frameshift alteration segregated with HCM in the father and paternal grandmother (Schaefer E et al. Eur J Med Genet, 2014 Mar;57:129-32). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at