11-47347860-C-T

Position:

chr11-47347860-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000256.3(MYBPC3):c.818G>A(p.Arg273His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000722 in 1,565,784 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:16

Conservation

PhyloP100: 3.42

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	7/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	7/35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.818G>A	p.Arg273His	missense_variant	7/34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 linkuse as main transcript	n.818G>A		non_coding_transcript_exon_variant	7/27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000918

AC:

AN:

174260

Hom.:

AF XY:

0.0000643

AC XY:

AN XY:

93312

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000228

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000847

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000778

AC:

110

AN:

1413622

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

698642

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.000241

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000543

Gnomad4 SAS exome

AF:

0.0000875

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000170

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2016	The R273H variant of uncertain significance in the MYBPC3 gene was first reported in a middle-agedproband with familial HCM and her affected teenage son (Ingles et al., 2005). Both proband and soneach harbored a second variant in the MYH7 gene; the proband's clinically unaffected teenage daughterwas heterozygous for only the R273H variant (Ingles et al., 2005). Subsequently, Olivotto et al.(2008) reported another individual with HCM who harbored R273H. The R273H variant was notobserved with any significant frequency in the NHLBI Exome Sequencing Project or in the ExomeAggregation Consortium (ExAC). However, R273H is a conservative amino acid substitution, which isnot likely to impact secondary protein structure as these residues share similar properties. In addition,this substitution occurs at a position that is not conserved. Nevertheless, in silico analysis predicts thisvariant is probably damaging to the protein structure/function. Finally, a missense variant at the sameresidue (R273C) has been reported in the Human Gene Mutation Database in association with HCM(Stenson et al., 2014); however, the pathogenicity of this variant has not been definitivelydetermined.Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family memberscreening at this time. -

Hypertrophic cardiomyopathy

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This missense variant replaces arginine with histidine at codon 273 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 27532257) and in an individual affected with dilated cardiomyopathy (PMID: 27532257). This variant has also been reported in two related individuals affected with hypertrophic cardiomyopathy, who carried a pathogenic p.Arg719Gln variant in the same gene that could explain the observed phenotype (PMID: 16199542). A relative from this family who carried this variant and lacked the pathogenic p.Arg719Gln variant was unaffected (PMID: 16199542). This variant has been identified in 16/174260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 273 of the MYBPC3 protein (p.Arg273His). This variant is present in population databases (rs376461745, gnomAD 0.02%). This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 16199542, 21835320, 27532257, 31513939). ClinVar contains an entry for this variant (Variation ID: 161312). 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.Arg273 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 21425739), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 24, 2023	This missense variant replaces arginine with histidine at codon 273 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 four individuals affected with hypertrophic cardiomyopathy (PMID: 16199542, 27532257, 31513939, 32841044). One of these individuals also carried a pathogenic variant in the MYH7 gene; a relative from this family who carried this variant and lacked the pathogenic MYH7 variant was unaffected (PMID: 16199542). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 27532257, 31983221) and in one individual affected with primary cardiomyopathy (PMID: 37477868). This variant has been identified in 16/174260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 27, 2016	- -

Hypertrophic cardiomyopathy 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Cardiomyopathy, familial hypertrophic, 4, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2-Supporting => PM2 downgraded in strength to Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The MYBPC3 c.818G>A (p.Arg273His) missense variant has been reported in at least three studies in which it was found in a heterozygous state in three patients with hypertrophic cardiomyopathy (Ingles et al. 2005; Olivotto et al. 2011; Coppini et al. 2014). One of the patients also carried a heterozygous missense variant in the MYH7 gene. The MYBPC3 p.Arg273His variant was also found in a heterozygous state in an unaffected individual from the same family (Ingles et al. 2005). The p.Arg273His variant was absent from 600 control chromosomes and is reported at a frequency of 0.00012 in the South Asian population of the Exome Aggregation Consortium, but this is based on one allele only in a region of low sequence coverage. The p.Arg273 residue is conserved. The evidence for this variant is limited. The p.Arg273His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for familial hypertrophic cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The p.R273H variant (also known as c.818G>A), located in coding exon 7 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 818. The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This variant co-occurred with an MYH7 pathogenic mutation in two individuals with hypertrophic cardiomyopathy (HCM) in a family; however, a third relative with only the MYBPC3 variant was unaffected at the time of study (Ingles J et al. J Med Genet. 2005 Oct;42(10):e59). This variant has also been detected in HCM cohorts, or cohorts referred for HCM or dilated cardiomyopathy genetic testing; however, details were limited (Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Olivotto I et al. J Am Coll Cardiol, 2011 Aug;58:839-48; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Walsh R et al. Genet Med, 2017 02;19:192-203; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jul 03, 2015

This MYBPC3 Arg273His variant has been described by Olivotto I., et al (2011) in a proband with HCM and is a singleton event in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in one HCM proband who was diagnosed with HCM aged 13 years who required heart transplantation (Ingles J., et al 2005). This proband also carries an addtional pathogenic MYH7 (Arg719Gln) variant. Limited segregation data from our laboratory identified the proband's clinically affected son carried both the MYH7 and MYBPC3 variants. The proband's clinically unaffected son carries this MYBPC3 Arg273His variant only. Computational analyses (SIFT, Polyphen2, MutationTaster and CADD) are supportive of a possibly deleterious effect. More evidence and additional data is needed to confirm the role of this variant in disease. Thus, we classify this variant as of "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Uncertain

0.41

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T;T

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.1

M;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.86

MVP

0.88

MPC

0.89

ClinPred

0.62

GERP RS

4.6

Varity_R

0.47

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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