rs730880623

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000256.3(MYBPC3):c.604A>C(p.Lys202Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,611,404 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K202R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 8.01

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.604A>C	p.Lys202Gln	missense_variant	Exon 5 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYBPC3	ENST00000545968.6 link	c.604A>C	p.Lys202Gln	missense_variant	Exon 5 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.604A>C	p.Lys202Gln	missense_variant	Exon 5 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1 link	n.604A>C		non_coding_transcript_exon_variant	Exon 5 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152268

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000367

AC:

AN:

245380

AF XY:

0.0000449

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000805

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000507

AC:

AN:

1459136

Hom.:

Cov.:

AF XY:

0.0000482

AC XY:

AN XY:

725960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000657

AC:

AN:

1111692

Other (OTH)

AF:

0.0000166

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000935

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Lys202Gln variant in MYBPC3 has been reported in 1 individual with DCM. This variant has also been identified in 5/62340 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs730880623). Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Lys202Gln variant is uncertain.

Apr 24, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYBPC3: PM2

Feb 28, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with DCM in the published literature and in a participant in the Framington Heart Study (PMID: 20215591, 28679633, 31931689, 31983221, 22958901); 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: 22958901, 31931689, 28679633, 31983221, 20215591)

Hypertrophic cardiomyopathy

Uncertain:2

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 202 of the MYBPC3 protein (p.Lys202Gln). This variant is present in population databases (rs730880623, gnomAD 0.008%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20215591, 31931689, 31983221). ClinVar contains an entry for this variant (Variation ID: 181046). 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.

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces lysine with glutamine at codon 202 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 20215591, 31983221). This variant has also been identified in 10/276772 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.

Cardiomyopathy

Uncertain:1

Jun 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces lysine with glutamine at codon 202 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 several individuals affected with dilated cardiomyopathy (PMID: 20215591, 31983221, 38489124). This variant has been identified in 10/276772 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.

Dilated cardiomyopathy 1A

Uncertain:1

May 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Uncertain:1

Mar 14, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.K202Q variant (also known as c.604A>C), located in coding exon 5 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 604. The lysine at codon 202 is replaced by glutamine, an amino acid with similar properties. This alteration has been detected in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Hershberger RE et al. Circ Cardiovasc Genet. 2010;3:155-61; Mazzarotto F et al. Circulation, 2020 02;141:387-398; Ramchand J et al. J Am Heart Assoc, 2020 01;9:e013346). This variant has also been identified in individuals without overt clinical features of DCM (Bick AG et al. Am. J. Hum. Genet. 2012;91:513-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

MYBPC3-related disorder

Uncertain:1

Sep 28, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MYBPC3 c.604A>C variant is predicted to result in the amino acid substitution p.Lys202Gln. This variant has been reported in individuals with dilated cardiomyopathy (Hershberger et al. 2010. PubMed ID: 20215591; Dataset S6, Ito et al. 2017. PubMed ID: 28679633; Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221; Table S2, Bick et al. 2012. PubMed ID: 22958901; Table S4, Ramchand et al. 2020. PubMed ID: 31931689). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47371375-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Uncertain

0.54

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.6

M;.;.

PhyloP100

8.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.82

ClinPred

0.66

GERP RS

4.8

Varity_R

0.76

gMVP

0.73

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over