rs397515891

Variant names:

• chr11-47343264-T-C
• rs397515891
• NM_000256.3:c.1224-2A>G

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.1224-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,409,368 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.12

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 7.843137E-4 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 11-47343264-T-C is Pathogenic according to our data. Variant chr11-47343264-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343264-T-C is described in Lovd as [Pathogenic]. Variant chr11-47343264-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1224-2A>G		splice_acceptor_variant, intron_variant	Intron 13 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1224-2A>G		splice_acceptor_variant, intron_variant	Intron 13 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1224-2A>G		splice_acceptor_variant, intron_variant	Intron 12 of 33	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1224-2A>G		splice_acceptor_variant, intron_variant	Intron 13 of 26	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1409368 Hom.: 0 Cov.: 41 AF XY: 0.00000144 AC XY: 1 AN XY: 696314

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: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

May 06, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published RNA studies demonstrate disruption of the canonical splice acceptor site of exon 14, resulting in a shift in reading frame and creation of a premature termination codon in exon 15; loss-of-function is a known mechanism of disease for this gene (PMID: 18337725); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22267749, 27532257, 28986452, 18337725, 29998127, 12707239, 33906374, 37652022) -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 IVS13-2 A>G Based on the data reviewed below we consider this variant likely disease-causing. The variant has been seen in at least one unrelated case of HCM (Page et al., 2012) . Page and colleagues studied 585 consecutive, unrelated probands with HCM and noted one individual heterozygous for the above variant. Details on the phenotype of this individual were not given. In order to classify this variant as a disease-causing mutation for this paper, Page and colleagues analyzed RNA although specifics about the protein function of this particular variant was not given. No segregation data was provided. This variant was absent in 384 UK controls and 200 Danish controls. The c.1224-2 A>G variant destroys the canonical splice acceptor site in intron 13 and is predicted to cause abnormal gene splicing. The variant is predictive to lead to either an abnormal message that is subject to nonsence-mediated mRNA decay or to an abnormal protein product if the message is used for protein translation. Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003), and splice variants in MYBPC3 are a well-established cause of HCM. MYBPC3 splice variants reported in association with HCM include IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A). In total the variant has not been seen in ~7084 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at IVS13-2 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/10/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 7/10/13). The variant was not observed in the following laboratory and published control samples: Page et al., 2012 384 UK control and 200 Danish controls. -

Hypertrophic cardiomyopathy Pathogenic:2

Oct 28, 2006

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 13 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: 12707239, 27532257; Invitae). This variant is also known as IVS14–2:a10385g. ClinVar contains an entry for this variant (Variation ID: 42511). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Aug 11, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1224-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 14 in the MYBPC3 gene. This variant has been detected in individuals with features consistent with hypertrophic cardiomyopathy (Richard P et al. Circulation, 2003 May;107:2227-32; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Frank-Hansen R et al. Eur J Hum Genet, 2008 Sep;16:1062-9; Ware SM et al. J Am Heart Assoc, 2021 May;10:e017731; Ambry internal data). RNA studies by one group have demonstrated that this alteration results in abnormal splicing resulting in a frameshift and premature truncation (Frank-Hansen R et al. Eur J Hum Genet, 2008 Sep;16:1062-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site. In addition to the clinical data presented in the literature alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.47		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: rs397515891; hg19: chr11-47364815;