11-47346636-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000256.3(MYBPC3):c.917G>A(p.Arg306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,534,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R306W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.734

Publications

7 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15450865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.917G>A	p.Arg306Gln	missense_variant	Exon 11 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYBPC3	ENST00000545968.6 link	c.917G>A	p.Arg306Gln	missense_variant	Exon 11 of 35	5	NM_000256.3	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6 link	c.917G>A	p.Arg306Gln	missense_variant	Exon 10 of 34	5		ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1 link	n.917G>A		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000139

AC:

AN:

144302

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000520

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

GnomAD2 exomes

AF:

0.0000307

AC:

AN:

228156

AF XY:

0.0000242

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.0000332

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000599

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000287

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1390304

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

688710

show subpopulations

African (AFR)

AF:

0.0000319

AC:

AN:

31360

American (AMR)

AF:

0.0000254

AC:

AN:

39412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24026

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38358

South Asian (SAS)

AF:

0.0000122

AC:

AN:

82062

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52268

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.0000170

AC:

AN:

1060044

Other (OTH)

AF:

0.00

AC:

AN:

57292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.0000139

AC:

AN:

144302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69894

show subpopulations

African (AFR)

AF:

0.0000520

AC:

AN:

38492

American (AMR)

AF:

0.00

AC:

AN:

14130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3408

East Asian (EAS)

AF:

0.00

AC:

AN:

4888

South Asian (SAS)

AF:

0.00

AC:

AN:

4536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66294

Other (OTH)

AF:

0.00

AC:

AN:

1974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000746

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000248

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 11, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Arg306Gln varia nt in MYBPC3 has now been identified by our laboratory in one individual with DC M and one individual with HCM. It has also been identified in 1/4036 African Am erican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washingt on.edu). Arginine (Arg) at position 306 is not evolutionarily conserved and the change to glutamine (Gln) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimat ed to be correct 89% of the time (Jordan 2011). Although these data support that the Arg306Gln variant is more likely benign, additional information is needed t o fully assess the clinical significance of this variant. -

Cardiomyopathy

Uncertain:1

Jan 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with glutamine at codon 306 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 25351510) and in one individual affected with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant has been identified in 7/228156 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. -

not provided

Uncertain:1

Jul 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient with cardiomyopathy in published literature (PMID: 27532257); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31983221, 27532257) -

Hypertrophic cardiomyopathy

Uncertain:1

Aug 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 306 of the MYBPC3 protein (p.Arg306Gln). This variant is present in population databases (rs373204728, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42802). 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 tolerated. 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. -

Cardiovascular phenotype

Benign:1

Mar 04, 2025

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostCm

Benign

0.018

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.10

T;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;.

PhyloP100

0.73

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.15

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.043

B;.;.

Vest4

0.36

MVP

0.73

MPC

0.26

ClinPred

0.030

GERP RS

4.0

Varity_R

0.094

gMVP

0.15

Mutation Taster

=89/11

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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