11-47348424-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.772G>A(p.Glu258Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000337 in 1,604,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000917820: Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E258Q) has been classified as Uncertain significance. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:34U:1

Conservation

PhyloP100: 7.86

Publications

90 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AD, AR 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
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy
Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

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ACMG classification

Specifications for MYBPC3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000917820: Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014).; SCV000208245: Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); SCV000996340: Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013).; SCV001434957: mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304).; SCV004014736: Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194).; SCV005398702: Functional studies showed exon 6 skipping resulting in p.(Val219Argfs*42), predicted to undergo nonsense-mediated decay (NMD) (PMIDs: 15114369, 25031304); SCV000059319: Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009).; SCV000260690: Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15114369, 19574547, 25031304).; SCV001572568: "In murine a-engineered cardiac tissue the variant resulted in accelerated contractile kinetics, disruption of twitch force and absence of the interaction between cMyBP-C and myosin heavy chain sub-fragment 2" (PMID: 23980194).; SCV004175449: "Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein" (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044); SCV004834726: RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19590044). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194).; SCV000320235: RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43).; SCV003925302: "In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]."; SCV001359738: RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19590044). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 11-47348424-C-T is Pathogenic according to our data. Variant chr11-47348424-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.772G>A	p.Glu258Lys	missense splice_region	Exon 6 of 35	NP_000247.2	Q14896-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.772G>A	p.Glu258Lys	missense splice_region	Exon 6 of 35	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6	TSL:5	c.772G>A	p.Glu258Lys	missense splice_region	Exon 6 of 34	ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1	TSL:5	n.772G>A		splice_region non_coding_transcript_exon	Exon 6 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000166

AC:

AN:

241524

AF XY:

0.0000229

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:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1452256

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

722342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33312

American (AMR)

AF:

0.0000227

AC:

AN:

44056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.00

AC:

AN:

85424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000416

AC:

AN:

1104986

Other (OTH)

AF:

0.0000333

AC:

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000181

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 4 (12)

not provided (8)

Hypertrophic cardiomyopathy (6)

Cardiomyopathy (2)

Cardiovascular phenotype (2)

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (2)

Primary familial hypertrophic cardiomyopathy (2)

Left ventricular noncompaction 10 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

CardioboostCm

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.7

PhyloP100

7.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.62

Sift

Benign

0.047

Sift4G

Benign

0.069

Polyphen

0.79

Vest4

0.95

MutPred

0.85

Gain of ubiquitination at E258 (P = 0.0121)

MVP

0.90

MPC

0.79

ClinPred

0.94

GERP RS

5.1

Varity_R

0.46

gMVP

0.64

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.17

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over