11-47343496-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000256.3(MYBPC3):c.1219G>C(p.Gly407Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,437,384 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. G407S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.38

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.1219G>C	p.Gly407Arg	missense	Exon 13 of 35	NP_000247.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.1219G>C	p.Gly407Arg	missense	Exon 13 of 35	ENSP00000442795.1
MYBPC3	ENST00000399249.6	TSL:5	c.1219G>C	p.Gly407Arg	missense	Exon 12 of 34	ENSP00000382193.2
MYBPC3	ENST00000544791.1	TSL:5	n.1219G>C		non_coding_transcript_exon	Exon 13 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000475

AC:

AN:

210360

AF XY:

0.00000879

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000328

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000209

AC:

AN:

1437384

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32988

American (AMR)

AF:

0.0000485

AC:

AN:

41246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25580

East Asian (EAS)

AF:

0.00

AC:

AN:

38478

South Asian (SAS)

AF:

0.00

AC:

AN:

82320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100506

Other (OTH)

AF:

0.00

AC:

AN:

59528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wolff-Parkinson-White pattern

Uncertain:1

Jul 14, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

This variant was identified in an individual with Wolff-Parkinson-White syndrome

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Uncertain:1

Aug 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 407 of the MYBPC3 protein (p.Gly407Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Wolff-Parkinson-White syndrome (PMID: 32233023). ClinVar contains an entry for this variant (Variation ID: 487636). 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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

CardioboostCm

Benign

0.038

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.4

PhyloP100

7.4

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.34

Sift

Uncertain

0.022

Sift4G

Uncertain

0.040

Polyphen

0.91

Vest4

0.83

MutPred

0.27

Gain of catalytic residue at G407 (P = 0.0441)

MVP

0.90

MPC

0.84

ClinPred

0.95

GERP RS

5.0

Varity_R

0.23

gMVP

0.70

Mutation Taster

=13/87

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over