rs727504287

Positions:

• chr11-47342686-CCTT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:3
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Ig-like C2-type 3 (size 90) in uniprot entity MYPC3_HUMAN there are 33 pathogenic changes around while only 9 benign (79%) 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 [Likely_pathogenic]. Clinvar id is 177699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342686-CCTT-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.1513_1515del	p.Lys505del	inframe_deletion	17/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1513_1515del	p.Lys505del	inframe_deletion	17/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.1513_1515del	p.Lys505del	inframe_deletion	16/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.1513_1515del	p.Lys505del	inframe_deletion, NMD_transcript_variant	17/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249264 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461698 Hom.: 0 AF XY: 0.00000825 AC XY: 6 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:10 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	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	- -
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. -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, flagged submission	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2023	PM2_supporting, PM4, PS4 -
Uncertain significance, flagged submission	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 18, 2024	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. -
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, flagged submission

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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727504287; hg19: chr11-47364237;