rs727504235

Positions:

chr11-47333742-C-T

Variant summary

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

The NM_000256.3(MYBPC3):c.3005G>A(p.Arg1002Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000807 in 1,599,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1002W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:7

Conservation

PhyloP100: 5.79

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3005G>A	p.Arg1002Gln	missense_variant	29/35	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.3005G>A	p.Arg1002Gln	missense_variant	29/35	5	NM_000256.3	ENSP00000442795	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3005G>A	p.Arg1002Gln	missense_variant	28/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152210

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000551

AC:

AN:

235732

Hom.:

AF XY:

0.0000548

AC XY:

AN XY:

127816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000353

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000740

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000850

AC:

123

AN:

1447138

Hom.:

Cov.:

AF XY:

0.0000862

AC XY:

AN XY:

718856

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000906

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000995

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74490

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000728

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This missense variant replaces arginine with glutamine at codon 1002 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597; Burns, thesis 2019) and in an infant affected with sudden death (PMID: 28807990). This variant has also been identified in 16/267108 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	Oct 04, 2021	- -

Hypertrophic cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1002 of the MYBPC3 protein (p.Arg1002Gln). This variant is present in population databases (rs727504235, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MYBPC3-related conditions (PMID: 11815426, 27532257, 28790153, 28807990, 29030401, 33673806, 33782553). ClinVar contains an entry for this variant (Variation ID: 177622). 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. 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	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces arginine with glutamine at codon 1002 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 11815426, 28790153, 27532257, 32841044, 33495597; Burns, thesis 2019) and in an infant affected with sudden death (PMID: 28807990). This variant has also been identified in 16/267108 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. -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Blueprint Genetics

Jan 26, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 05, 2019

The p.Arg1002Gln variant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 2009 and LVOD unpublished data). This variant was also identified by our laboratory in 1 individual with DCM and in 1 individual with giant right atrium and arrhythmia (LMM unpublished data). In addition, this variant was identified in 4/62092 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolutionarily distant species and the change to glutamine (Gln) is present in several birds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign.,The Arg1002Gln variant in MYBPC3 has been reported in 3 individuals with HCM (Niimura 2002, Ho 2009 and LVOD unpublished data). This variant was also identified by our laboratory in 1 individual with DCM and in 1 individual with giant right atrium and arrhythmia (LMM unpublished data). In addition, this variant was identified in 4/62092 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Arginine (Arg) at position 1002 is not conserved in evolutionarily distant species and the change to glutamine (Gln) is present in several birds. Additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Arg1002Gln variant is uncertain, the presence of the variant amino acid in multiple bird species suggests that it is more likely to be benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2023

Reported in individuals with HCM and DCM, and in one individual with sudden unexplained death in infancy (Niimura et al., 2002; Ho et al., 2009; Coppini et al., 2014; Burns et al, 2017; Walsh et al., 2017; Cirino et al., 2017; Dewar et al., 2017); 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: 21415409, 15115610, 24503780, 11815426, 20031602, 28790153, 28679633, 29030401, 25524337, 28807990, 27532257, 28986452, 33782553, KrylovaNS2020, 33673806, 35653365) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2022

The p.R1002Q variant (also known as c.3005G>A), located in coding exon 29 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3005. The arginine at codon 1002 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been detected in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and sudden unexplained death (SUD) cohorts; however, clinical details are limited (Niimura H et al. Circulation, 2002 Jan;105:446-51; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10; Dewar LJ et al. Circ Cardiovasc Genet, 2017 Aug;10; Ho CY et al. Circ Cardiovasc Genet, 2009 Aug;2:314-21; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Cirino AL et al. Circ Cardiovasc Genet, 2017 Oct;10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Oakley CE et al. Cell Res., 2004 Apr;14:95-110). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

CardioboostCm

Uncertain

0.76

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.5

D;.;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0050

D;.;D

Sift4G

Uncertain

0.029

D;D;D

Vest4

0.91

MVP

0.86

MPC

0.89

ClinPred

0.83

GERP RS

5.0

Varity_R

0.52

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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