11-47347852-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.821+5G>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYBPC3
NM_000256.3 splice_region, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:2

Conservation

PhyloP100: 6.19

Publications

5 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: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

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

PP5

Variant 11-47347852-C-T is Pathogenic according to our data. Variant chr11-47347852-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.821+5G>A		splice_region_variant, intron_variant	Intron 7 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
MYBPC3	ENST00000545968.6 link	c.821+5G>A	splice_region_variant, intron_variant	Intron 7 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6 link	c.821+5G>A	splice_region_variant, intron_variant	Intron 7 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1 link	n.821+5G>A	splice_region_variant, intron_variant	Intron 7 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1411554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697410

African (AFR)

AF:

0.00

AC:

AN:

32166

American (AMR)

AF:

0.00

AC:

AN:

37042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25318

East Asian (EAS)

AF:

0.00

AC:

AN:

36646

South Asian (SAS)

AF:

0.00

AC:

AN:

79854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086572

Other (OTH)

AF:

0.00

AC:

AN:

58524

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000439

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 4

Pathogenic:3Uncertain:1

Mar 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 14, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Jan 01, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PP3, PP5 -

Hypertrophic cardiomyopathy

Pathogenic:3

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 7 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 9048664, 12707239, 23140321). This variant is also known as IVS7+5G>A. ClinVar contains an entry for this variant (Variation ID: 42796). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 9048664). For these reasons, this variant has been classified as Pathogenic. -

Jun 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The 821+5G>A variant in MYBPC3 has been reported in 2 individuals with HCM, was absent from 400 control chromosomes, and segregated with disease in 4 affected r elatives from 1 family (Carrier 1997, Richard 2003). In addition, this variant h as been identified by our laboratory in 2 Caucasian adults with HCM. This varian t is located in the 5' splice region and in vitro studies indicate this variant leads to aberrant splicing which is predicted to result in a truncated or absent protein (Carrier 1997, Flavigny 1999, Flavigny 2003). In summary, segregation a nd in vitro studies suggest that this variant is likely pathogenic, though addit ional studies are required to fully establish its clinical significance. -

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2Uncertain:1

Jul 04, 2017

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 07, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate that this variant leads to exon skipping and premature truncation (Carrier et al., 1997; Flavigny et al., 1999; Ito et al., 2017); Reported in ClinVar (ClinVar Variant ID# 42796; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31513939, 24721642, 28679633, 10610770, 9048664, 20624503, 12707239, 14613868, 30847666, 33673806) -

Cardiomyopathy

Pathogenic:1

Feb 02, 2017

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

6.2

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.86

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.86

Position offset: 5

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over