rs397515963

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_000256.3(MYBPC3):c.2373dupG(p.Trp792ValfsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,563,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000299248: Functional studies demonstrate that this variant causes abberrant phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (PMID:19273718 )." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay. The gene MYBPC3 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:41O:1

Conservation

PhyloP100: 0.107

Publications

73 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:

Genome browser will be placed here

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 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000299248: Functional studies demonstrate that this variant causes abberrant phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (PMID: 19273718 ).; SCV001367637: PS3; SCV005398155: "This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs expressed in mouse MYBPC3 KO engineered heart tissues displayed significantly different maximal force, contraction and relaxation kinetics, and external Ca2+ sensitivities compared with WT constructs. Moreover, mutant constructs were unable to rescue the MYBPC3 KO phenotype when expressed in either homozygous and heterozygous states." PMID:27108529; SCV005911682: Functional studies of this variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (PMID:10736283).; SCV000917818: At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating data that supports this variant causing loss-of-function (Van Dijk_2009).; SCV000059136: "In vitro functional studies support that this variant leads to a loss-of-function." PMID:10736283; SCV001572570: Functional studies demonstrated that the variant reduced maximal force-generating capacity of cardiomyocytes(PS3) (PMID: 19273718).; SCV004842354: A homozygous mouse model for this variant has shown a phenotype consistent with end-stage hypertrophic cardiomyopathy, severe cardiac hypertrophy, and cardiac dysfunction (PMID: 37844837).; SCV000208297: Published functional studies demonstrate c.2373dupG causes haploinsufficiency, deranged phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (van Dijk et al., 2009); SCV003799249: Functional analyses of the variant protein show use of the cryptic splice site, leading to a frameshift and haploinsufficiency (Moolman 2000, van Dijk 2009). PMID: 10736283 PMID: 19273718; SCV000318483: Multiple functional studies have reported this mutation to result in loss of function (Moolman, 2000; van Dijk, 2009; Marston, 2012; Wijnker, 2016).; SCV001344628: A homozygous mouse model for this variant has shown a phenotype consistent with end-stage hypertrophic cardiomyopathy, severe cardiac hypertrophy, and cardiac dysfunction (PMID: 37844837).

PP5

Variant 11-47337729-A-AC is Pathogenic according to our data. Variant chr11-47337729-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 42619.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.2373dupG	p.Trp792ValfsTer41	frameshift	Exon 24 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.2373dupG	p.Trp792ValfsTer41	frameshift	Exon 24 of 35	ENSP00000442795.1	Q14896-1
MYBPC3	ENST00000399249.6	TSL:5	c.2373dupG	p.Trp792ValfsTer41	frameshift	Exon 23 of 34	ENSP00000382193.2	A8MXZ9
MYBPC3	ENST00000544791.1	TSL:5	n.2373dupG		non_coding_transcript_exon	Exon 24 of 27	ENSP00000444259.1	F5GZR4

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151760

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000174

AC:

AN:

172018

AF XY:

0.0000109

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:

0.0000428

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

1412080

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

697906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32130

American (AMR)

AF:

0.00

AC:

AN:

37104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25310

East Asian (EAS)

AF:

0.00

AC:

AN:

36644

South Asian (SAS)

AF:

0.00

AC:

AN:

80546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000350

AC:

AN:

1086342

Other (OTH)

AF:

0.0000171

AC:

AN:

58584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000198

AC:

AN:

151760

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41284

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.0000453

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypertrophic cardiomyopathy 4 (14)

not provided (12)

Hypertrophic cardiomyopathy (7)

Cardiomyopathy (2)

Cardiovascular phenotype (2)

Primary familial hypertrophic cardiomyopathy (2)

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 (1)

MYBPC3-related disorder (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.11

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: 1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over