11-47342697-C-T

Position:

• chr11-47342697-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1505G>A​(p.Arg502Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 5.79

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 14 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47342698-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 11-47342697-C-T is Pathogenic according to our data. Variant chr11-47342697-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342697-C-T is described in Lovd as [Pathogenic]. Variant chr11-47342697-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1505G>A	p.Arg502Gln	missense_variant	17/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1505G>A	p.Arg502Gln	missense_variant	17/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1505G>A	p.Arg502Gln	missense_variant	16/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1505G>A		non_coding_transcript_exon_variant	17/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

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

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 28, 2017	- -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 09, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 22, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Arg502Gln Based on the data reviewed below, we consider this variant very likely disease causing. This variant has been seen in at least 9 unrelated cases of HCM with moderately strong segregation data in two different families. Niimura et al (1998) first reported the variant in two families with HCM. The variant segregated with disease in 4 members of one family and 5 members of the other, with the furthest degree of relationship between affecteds with the variant in each family being 2nd degree. Cardim et al (2005) observed the variant in a Portugese patient with HCM. Rudzinski et al (2008) observed the variant in one Polish HCM patient. Girolami et al (2006) observed the variant in two unrelated patients with HCM (likely the same two families in Olivotto et al 2008). Morita et al (2008) observed p.Arg502Gln in a child with HCM. A German group observed the variant in one patient with HCM (Ehlermann et al 2008). This may be the same case reported in a methods paper by Zeller et al (2006). Rodriguez-Garcia et al (2010) observed the variant in two unrelated Spanish families with HCM and in one of those families there were two affected individuals with the variant. The arginine at codon 502 is highly conserved. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Another variant (p.Arg502Trp) at the same codon, which we consider very likely disease causing, was recently reported as the most common HCM-causing variant with a frequency of 2.4% in HCM patients (Saltzman et al 2010). Variants in nearby codons have also been reported in association with HCM (p.Arg495Gln, p.Lys505del, p.Gly507Arg). In total the variant has not been seen in ~418 published controls: 100 (Niimura et al 1998), 118 (Rudzinski et al 2008), 200 (Rodriguez-Garcia et al 2010). p.Arg502Gln is not listed in the NHLBI Exome Sequencing Project dataset, however, p.Arg502Trp was observed in 1 of 3472 Caucasians and 0 of 1826 Caucasians in that dataset (as of 1/16/2012). Individual phenotypes from that dataset are not available. Several different cohorts from studies on common complex cardiovascular disease were pooled to create that sample. There is no variant at codon 502 listed in dbSNP or 1000 genomes (as of 1/16/2012). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20298698, 15115610, 20378854, 32952175, 34097875, 34060810, 16715312, 31918855, 27532257, 18803133, 25342278, 22386539, 27600940, 26507537, 26183555, 25892673, 18957093, 22857948, 24093860, 24510615, 20433692, 22112859, 18403758, 16566405, 16858239, 18533079, 17224687, 22267749, 30645170, 29687901, 20738943, 29907873, 28166811, 21310275, 28193612, 31006259, 31447099, 30847666, 33658040, 9562578, 31589614, 12106841, 33407484, 34400558, 35208637, 36243179, 36264615, 36252119, 36136372, 35653365, 12707239) -

Hypertrophic cardiomyopathy 4 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cardiomyopathy. (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset hypertrophic and dilated cardiomyopathies, however recessive inheritance is associated with a severe early onset hypertrophic cardiomyopathy (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (13 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated immunoglobulin I-set domain (NCBI). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (ClinVar, PMID: 31308319, 31771441). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM5+PM2_Supporting+PP3+PS4+PP1_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jun 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042541, PMID:9562578, PS1_S). A different missense change at the same codon has been reported to be associated with MYBPC3 related disorder (ClinVar ID: VCV000042540, PMID:12707239,26090888, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.645, 3CNET: 0.973, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 28, 2017	The p.Arg502Gln variant in MYBPC3 has been identified in at least 15 individuals with HCM and segregated with disease in 8 affected relatives from 3 families (N iimura 1998, Olivotto 2008, Rodriguez-Garcia 2010, Otsuka 2012, LMM data). It ha s also been reported by other clinical laboratories in ClinVar (Variation ID 425 41) and was absent from large population studies. Another missense variant in t he same codon (p.Arg502Trp) is one of the most common pathogenic MYBPC3 variants associated with HCM, supporting that this codon is critical for MYBPC3 protein function. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affecte d individuals, segregation studies, absence from the general population, and occ urrence in a critical codon. ACMG/AMP criteria applied (Richards 2015): PS4, PP1 _Strong, PM5, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jan 08, 2018	This heterozygous missense variant in the MYBPC3 gene was identified in a baby with neonatal hypertrophic cardiomyopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 24, 2024	This missense variant replaces arginine with glutamine at codon 502 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 16566405, 18403758, 18533079, 20433692, 22112859, 22267749, 22857948, 27600940, 28193612, 31308319). It has been shown that this variant segregates with hypertrophic cardiomyopathy in multiple affected individuals across multiple unrelated families (PMID: 20433692, 22112859). This variant has also been reported in one individual affected with left ventricular noncompaction cardiomyopathy who also carried a different pathogenic truncation variant in the same gene (PMID: 31918855). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg502Trp, is considered to be disease-causing (ClinVar variation ID: 42540), suggesting that arginine at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jun 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 502 of the MYBPC3 protein (p.Arg502Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9562578, 16566405, 18403758, 18533079, 20433692, 22386539). ClinVar contains an entry for this variant (Variation ID: 42541). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg502 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 20378854, 22267749, 23396983). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 20, 2019	This missense variant replaces arginine with glutamine at codon 502 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have a deleterious impact on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 20433692, 22112859, 9562578, 16566405, 18403758, 18533079, 20433692, 22267749, 22857948, 27600940, 28193612). It has been shown that this variant segregates with hypertrophic cardiomyopathy in multiple unrelated families (PMID: 20433692, 22112859). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg502Trp, is known to be disease-causing (Clinvar variation ID 42540), indicating that arginine at this position is important for protein function. Based on available evidence, this variant is classified as Pathogenic. -

Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 2023

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 07, 2022

Variant summary: MYBPC3 c.1505G>A (p.Arg502Gln) results in a conservative amino acid change located in the immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250000 control chromosomes (gnomAD and publications). c.1505G>A has been reported in the literature in many individuals affected with Hypertrophic Cardiomyopathy (HCM), including in several unrelated families where it primarily segregated with the disease phenotype (e.g. Niimura_1998, Girolami_2006, Miller_2007, Morita_2008, Rodriguez-Garcia_2010, Otsuka_2012, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. A variant affecting the same codon, p.Arg502Trp, has also been reported to be associated with HCM, suggesting that the Arg502 residue is likely important for MYBPC3 protein function. Fourteen submitters have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

The p.R502Q pathogenic mutation (also known as c.1505G>A) is located in coding exon 17 of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1505. The arginine at codon 502 is replaced by glutamine, an amino acid with highly similar properties. This mutation has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM) including several families with strong evidence of segregation with disease (Nimura etal. N Engl J Med. 1998;338:1248-1257; Cardmin N etal. Rev Port Cardiol. 2005;24:1463-147; Rudzinski T etal. Kardiol Pol. 2008;66:821-825; Otsuka H et al. Circ. J. 2012;76(2):453-61; Maurizi N et al. JAMA Cardiol. 2018;3(6):520-525). This alteration has also been reported in an individual with HCM who also had evidence of left ventricular noncompaction (Faria R etal. Rev Port Cardiol. 2012;31:317-319). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

MYBPC3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2024

The MYBPC3 c.1505G>A variant is predicted to result in the amino acid substitution p.Arg502Gln. This variant has been reported to segregate with hypertrophic cardiomyopathy in multiple unrelated families (See for example – Niimura et al. 1998. PubMed ID: 9562578; Jordan et al. 2011. PubMed ID: 21310275; Table S1A/B in Walsh et al. 2017. PubMed ID: 27532257) and has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42541/). Additionally, different amino acid substitutions (p.Arg502Gly, p.Arg502Trp, p.Arg502Leu) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). We classify the c.1505G>A (p.Arg502Gln) variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.83
MVP		0.86
MPC		0.88
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.59
gMVP		0.68

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: rs397515907; hg19: chr11-47364248;