chr11-47338519-C-T

Variant names:

• chr11-47338519-C-T
• rs112738974
• NM_000256.3:c.2308+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2308+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47338519-C-T is Pathogenic according to our data. Variant chr11-47338519-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47338519-C-T is described in Lovd as [Pathogenic]. Variant chr11-47338519-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2308+1G>A		splice_donor_variant, intron_variant	Intron 23 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2308+1G>A		splice_donor_variant, intron_variant	Intron 23 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2308+1G>A		splice_donor_variant, intron_variant	Intron 22 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2308+1G>A		splice_donor_variant, intron_variant	Intron 23 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jul 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Haplotype analysis supported a founder effect for this variant in individuals from Spain (PMID: 28687478); Canonical splice site variant demonstrated to result in loss of function with skipping of exon 23 (PMID: 9048664); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25637381, 25525159, 27532257, 30550750, 30847666, 31513939, 16199542, 18957093, 24510615, 20439259, 12707239, 29247119, 28029522, 31589614, 33673806, 9048664, 38406555, 37652022, 36243179, 21088121, 26914223, 28687478) -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PM2_supporting, PS4_moderate, PVS1 -

Hypertrophic cardiomyopathy Pathogenic:4

Aug 11, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 2308+1A>G variant has ben reported in a large number of individuals with HCM and was absent from at least 1000 control chromosomes tested (Oliva-Sandoval 20 10, Richard 2003, Carrier 1997, Ehlermann 2008, Gandjbakch 2010). This variant is predicted to cause abnormal splicing because the nucleotide substitution occ urs in the highly conserved splice consensus sequence. Abnormal splicing can le ad to loss of function of the affected allele, which is an established disease m echanism for the MYBPC3 HCM patients. In summary, this variant meets our criteri a for pathogenicity (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls and prevalence of loss of function variants in HCM pat ients. -

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 23 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional mRNA study demonstrated splice site inactivation and skipping of exon 23, generating a truncated and prematurely terminated protein product (PMID: 9048664). This variant has been reported in over twenty individuals affected with hypertrophic cardiomyopathy (PMID: 9048664, 18957093, 21088121, 9048664, 18957093, 21088121). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 9048664, 18957093, 21088121). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Sep 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 23 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9048664, 12707239, 18957093, 21088121). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS23+1G>A. ClinVar contains an entry for this variant (Variation ID: 42610). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:2

Nov 18, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the +1 position of intron 23 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A functional mRNA study demonstrated splice site inactivation and skipping of exon 23, generating a truncated and prematurely terminated protein product (PMID: 9048664). This variant has been reported in over twenty individuals affected with hypertrophic cardiomyopathy (PMID: 9048664, 18957093, 21088121, 9048664, 18957093, 21088121). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 9048664, 18957093, 21088121). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jun 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYBPC3 c.2308+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. This impact on mRNA splicing was experimentally confirmed using patient lymphocytes (Carrier_1997, Sabater-Molina_2017). The variant was absent in 249118 control chromosomes (gnomAD). c.2308+1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy, and segregated with disease within pedigrees where family history was available (e.g. Carrier_1997, Ehlermann_2008, Sabater-Molina_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9048664, 18957093, 28029522). Six ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:2

Mar 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 31, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:2

Nov 27, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Apr 21, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 8
DS_DL_spliceai		0.93		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs112738974; hg19: chr11-47360070;