11-47337796-T-C

Position:

• chr11-47337796-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2309-2A>G variant causes a splice acceptor, 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: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.67

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027189542 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47337796-T-C is Pathogenic according to our data. Variant chr11-47337796-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 42613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337796-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2309-2A>G		splice_acceptor_variant, intron_variant		ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2309-2A>G		splice_acceptor_variant, intron_variant		5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2309-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.2309-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398394 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2022	Not observed in large population cohorts (gnomAD); Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 42613; ClinVar); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 34542152, 21302287, 27483260, 27532257, 15519027, 23782526, 27600940, 24704860, 25740977, 11815426, 25351510, 26656175, 25524337, 31589614, 32746448) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 06, 2018	- -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 28, 2024	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 15519027, 21302287, 24704860, 26656175, 27600940, 27483260, 31424582, 28408708). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	The c.2309-2A>G variant in MYBPC3 has been reported in 2 individuals with HCM an d was absent from 400 control chromosomes (Van Driest 2004, Roncarati 2011). Thi s variant has also been identified by our laboratory in 9 individuals with HCM a nd segregated with disease in two affected family members. This variant is locat ed in the invariant splice region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein . MYBPC3 variants resulting in a heterozygous loss of function are strongly ass ociated with HCM. In summary, this variant meets criteria to be classified as pa thogenic based upon the predicted impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change affects an acceptor 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: 15519027, 21302287, 24704860, 25740977, 27483260, 27600940). ClinVar contains an entry for this variant (Variation ID: 42613). 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

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 30, 2019	This variant causes an A>G nucleotide substitution at the canonical -2 position of intron 23 splice acceptor site of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 21302287, 24704860, 25740977, 27600940, 27483260; Clinvar variation ID 42613). 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. Based on the available evidence, this variant is classified as Pathogenic. -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 18, 2021

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Oct 26, 2021

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 01, 2019

Variant summary: MYBPC3 c.2309-2A>G 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 canonical a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 149798 control chromosomes. c.2309-2A>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Biagini_2014, Calore_2015, Coppini_2014, Girolami_2006, Nunez_2013, Roncarati_2011, VanDriest_2004, Witjas-Paalberends_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2021

The c.2309-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 24 in the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (Ambry internal data; Van Driest SL, J. Am. Coll. Cardiol. 2004 Nov; 44(9):1903-10; Roncarati R, J. Cell. Physiol. 2011 Nov; 226(11):2894-900; Lopes LR, Heart 2015 Feb; 101(4):294-301; Rubattu S et al. Int J Mol Sci. 2016;17(8); Walsh R et al Genet Med. 2017;19(2):192-203; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.74		Position offset: -11
DS_AL_spliceai		1.0		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs111729952; hg19: chr11-47359347;