11-47342719-G-A

Position:

chr11-47342719-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000256.3(MYBPC3):c.1483C>T(p.Arg495Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,880 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. R495G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 2.76

Variant links:

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]

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 chr11-47342719-G-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 11-47342719-G-A is Pathogenic according to our data. Variant chr11-47342719-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342719-G-A is described in Lovd as [Pathogenic]. Variant chr11-47342719-G-A is described in Lovd as [Likely_benign]. Variant chr11-47342719-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.1483C>T	p.Arg495Trp	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 linkuse as main transcript	c.1483C>T	p.Arg495Trp	missense_variant	17/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.1483C>T	p.Arg495Trp	missense_variant	16/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1 linkuse as main transcript	c.1483C>T	p.Arg495Trp	missense_variant, NMD_transcript_variant	17/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Likely pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 06, 2019	The MYBPC3 Arg495Trp variant has been reported in at least >10 HCM cases (see literature), and was found to segregate in one family (GarcÃa-Castro M, et al., 2009). We have identified this variant in a HCM proband of East Asian descent, with no family history of disease. The variant is present at a low frequency in the Genome Aggregation Database (AF=0.000007; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Furthermore different rare variants at this position (Arg495Gln and Arg495Gly) have been reported as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) the variant has been reported in more than 10 HCM probands (PS4_supporting), is rare in the general population (PM2), other amino acid changes at this position have been classified as pathogenic (PM5) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify MYBPC3 Arg495Trp as 'likely pathogenic'. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 495 of the MYBPC3 protein (p.Arg495Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 27532257). ClinVar contains an entry for this variant (Variation ID: 164114). 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.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11499718, 18403758, 19659763, 20019025, 20624503, 22857948, 23396983, 24093860, 27532257). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 09, 2023	This missense variant is located in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 unrelated individuals affected with hypertrophic cardiomyopathy and in a few asymptomatic relatives (PMID: 18713777, 19150014, 20433692, 23283745, 25351510, 27532257, 28356264, 28771489, 31919335, 32492895, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg495Gln and p.Arg495Gly, are known to be pathogenic (ClinVar variation ID: 164113, 42537), indicating that arginine at this position is important for the MYBPC3 protein function. 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	Apr 06, 2023	The p.Arg495Trp variant in MYBPC3 has been reported in at least 15 individuals with hypertrophic cardiomyopathy (HCM; Rodríguez-García 2010 PMID: 20433692, Coto 2012 PMID: 22765922, Rubattu 2016 PMID: 27483260, Walsh 2017 PMID: 27532257, Restrepo-Cordoba 2017 PMID: 28138913, Kim 2020 PMID: 32492895, Lipari 2020 PMID: 31919335, Sepp 2022 PMID: 35626289, LMM data), including in 1 individual who also had another pathogenic variant in MYBPC3 (Berge 2014 PMID: 24111713). This variant was also been identified by other clinical laboratories in ClinVar (Variation ID: 164114) and has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Additionally, a variant involving this codon (p.Arg495Gln) have been identified in individuals with HCM and has been classified as pathogenic by this laboratory. 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, PM2_Supporting, PM5. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy 4

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Oct 22, 2019	This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 19150014, 22765922, 27532257). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1483C>T (p.Arg495Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1483C>T (p.Arg495Trp) variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense variant c.1483C>T(p.Arg495Trp) in MYBPC3 gene has been observed in heterozygous state in multiple individuals with hypertrophic cardiomyopathy (Coto et. al., 2012; García-Castro et. al., 2009). The p.Arg495Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic / Likely_pathogenic (multiple submitters). The amino acid change p.Arg495Trp in MYBPC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant disrupts the p.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (Marsiglia JD et. al., 2013). The amino acid Arg at position 495 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 19, 2023	The MYBPC3 c.1483C>T (p.Arg495Trp) missense variant has been identified in a heterozygous state in at least five individuals with hypertrophic cardiomyopathy (PMID: 19150014; PMID: 22765922; PMID: 27532257). The variant has also been found in a heterozygous state in asymptomatic individuals suggesting reduced penetrance (PMID: 19150014). The c.1483C>T variant was not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, two different amino acid substitutions at the same codon [(p.Arg495Gln) and (p.Arg495Gly)] have been reported in individuals with hypertrophic cardiomyopathy (PMID: 27532257; ClinVar). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as pathogenic or likely pathogenic by at least three submitters in ClinVar. Based on the available evidence, the c.1483C>T (p.Arg495Trp) variant is classified as likely pathogenic for hypertrophic cardiomyopathy. -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2022	This missense variant is located in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 unrelated individuals affected with hypertrophic cardiomyopathy and in a few asymptomatic relatives (PMID: 18713777, 19150014, 20433692, 23283745, 25351510, 27532257, 28356264, 28771489, 31919335, 32492895, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at this codon, p.Arg495Gln and p.Arg495Gly, are known to be pathogenic (ClinVar variation ID: 164113, 42537), indicating that arginine at this position is important for the MYBPC3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 13, 2019

Variant summary: MYBPC3 c.1483C>T (p.Arg495Trp) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) domain and Immunoglobulin I-set (IPR013098) domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249906 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Garcia-Castro_2009, Coto_2012, Rodriguez-Garcia_2010, Walsh_2017). These data indicate that the variant may be associated with disease. However, this variant was also found in two asymptomatic family members (Garcia-Castro_2009), suggesting incomplete penetrance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense change at this codon has been classified as pathogenic by our laboratory (p.Arg495Gly). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The p.R495W variant (also known as c.1483C>T), located in coding exon 17 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1483. The arginine at codon 495 is replaced by tryptophan, an amino acid with dissimilar properties. In one family, this variant was detected in a proband and maternal grandfather both reported to have hypertrophy, and was also detected in the proband's unaffected mother (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56). This variant has also been detected in other probands reported to have hypertrophic cardiomyopathy (HCM) and in HCM cohorts where, in some cases, clinical detail was limited or another variant was also detected (Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart. 2015 Feb;101(4):294-301; Rubattu S et al. Int J Mol Sci, 2016 Jul;17(8); Walsh R et al. Genet. Med., 2017 02;19:192-203;Lipari M et al. Pol Arch Intern Med, 2020 02;130:89-99). This alteration was also reported in one individual from a dilated cardiomyopathy (DCM) cohort (Mazzarotto F et al. Circulation, 2020 02;141:387-398). Another alteration at the same codon, p.R495Q (c.1484G>A), has been reported in association with HCM (Niimura H et al. N. Engl. J. Med. 1998 Apr;338(18):1248-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

MYBPC3-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2024

The MYBPC3 c.1483C>T variant is predicted to result in the amino acid substitution p.Arg495Trp. This variant has been reported in several individuals with a diagnosis or clinical features consistent with hypertrophic cardiomyopathy (HCM) (see for example, García-Castro et al. 2009. PubMed ID: 19150014; Table 4, Coto et al. 2012. PubMed ID: 22765922; Table S2, Filatova et al. 2021. PubMed ID: 34598319; Table S8, McGurk et al. 2023. PubMed ID: 37652022) as well as an individual with dilated cardiomyopathy (DCM) (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221). It has also been reported in asymptomatic family members, suggestive of reduced penetrance (García-Castro et al. 2009. PubMed ID: 19150014). This variant has not been reported in a large population database, indicating this variant is rare. Alternate missense changes impacting the same amino acid (c.1483C>G; p.Arg495Gly and c.1484G>A; p.Arg495Gln) have been reported as pathogenic (Table S8, McGurk et al. 2023. PubMed ID: 37652022). Taken together, the c.1483C>T (p.Arg495Trp) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

CardioboostCm

Uncertain

0.62

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.74

D;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.5

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.010

D;.;D

Sift4G

Uncertain

0.0090

D;D;D

Vest4

0.97

MVP

0.90

MPC

0.85

ClinPred

0.99

GERP RS

3.7

Varity_R

0.44

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over