11-47335041-C-T

Variant names:

• chr11-47335041-C-T
• rs397515991
• NM_000256.3:c.2905+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2905+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000507 in 1,380,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 7.47
• Publications: 15 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.043921567 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 11-47335041-C-T is Pathogenic according to our data. Variant chr11-47335041-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 42666.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	c.2905+1G>A		splice_donor_variant, intron_variant	Intron 27 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2905+1G>A		splice_donor_variant, intron_variant	Intron 27 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2905+1G>A		splice_donor_variant, intron_variant	Intron 26 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000507 AC: 7 AN: 1380230 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 677072

African (AFR) AF: 0.00 AC: 0 AN: 31138

American (AMR) AF: 0.00 AC: 0 AN: 38092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22106

East Asian (EAS) AF: 0.00 AC: 0 AN: 37012

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.00000563 AC: 6 AN: 1065178

Other (OTH) AF: 0.00 AC: 0 AN: 56904

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jun 23, 2015

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 IVS27+1 G>A Based on the data reviewed below, we consider it very likely disease causing. Many protein-truncating variants have been reported in MYBPC3 in association with HCM (Erdmann et al. 2001 & 2003; Harvard Sarcomere Protein Gene Mutation Database), and splice variants in MYBPC3 are a well-established cause of HCM. Of note, similarly-positioned donor splice site mutations in at least 7 other exons have been reported to cause HCM: IVS7+1G>A, IVS8+1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). The G at this +1 consensus splice sequence site is completely conserved across vertebrate evolution. This specific variant has been previously seen in at least 3 unrelated families. Erdmann et al. reported IVS27+1 G>A in 2001 along with weak segregation data: The variant cosegregated with disease in 2 affected members of an HCM family, an affected mother and her affected son (it was also present in an unaffected daughter). An analysis of the mRNA in HCM patients’ lymphocytes confirmed the existence of abnormal splice products; IVS27+1 G>A led to in-frame skipping of exon 27 and the loss of 56 highly conserved amino acid residues that the researchers claim are important for incorporating myosin-binding protein C into the A band. Erdmann et al. (2003) reported that the IVS27+1 G>A variant was not present in more than 50 presumably healthy controls recruited in Germany. The variant is not reported in the NHLBI Exome Sequencing Project data set (http://evs.gs.washington.edu/EVS/), nor is a +1 donor splice site variant reported for any exon of MYBPC3 as of December 28, 2011. IVS27+1 G>A is not present in dbSNP (www.ncbi.nlm.nih.gov/SNP) or 1000 Genomes (http://browser.1000genomes.org/index.html). The 1000 Genomes samples from the Bushman population appear to contain some +1 G>A variants at other exons in the MYBPC3 gene, but this was not explored in depth. -

Jul 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Messenger RNA functional studies demonstrated in-frame skipping of exon 27, which was hypothesized to result in loss of 56 highly conserved amino acids residues that are important for the incorporation of myosin-binding protein C into the A band (Erdmann et al., 2001); An additional functional study demonstrated in-frame skipping of exon 27 led to creation of a premature termination codon at the junction of exons 26 and 28, which resulted in mRNA instability (Helms et al., 2014); Canonical splice donor site variant in intron 27 expected to result in aberrant splicing; This variant is associated with the following publications: (PMID: 30550750, 33673806, 26582918, 8834242, 27620334, 30456444, 34542152, 23074333, 25525159, 9241277, 27483260, 27532257, 29875314, 21959974, 25611685, 23396983, 25351510, 24510615, 28916354, 12974739, 31737537, 31447099, 21302287, 11499719, 25031304) -

Oct 13, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:3

Jul 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2905+1G>A variant in MYBPC3 has been reported in >10 individuals with HCM and segregated with disease in at least 3 affected members from two families (Ki mura 1997, Erdmann 2001, Walsh 2016, LMM unpublished data) and has also been rep orted in ClinVar (Variation ID 42666). It was absent from large population studi es. This variant occurs in the invariant region (+/- 1,2) of the splice consensu s sequence and has been shown to cause altered splicing in vitro and in vivo, le ading to an abnormal or absent protein (Erdmann 2001, Helms 2014). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, the c.2905+1G>A meets criteria to be classified as pathogenic for HC M in an autosomal dominant manner based upon presence in multiple affected indiv iduals, segregation and functional studies. -

Jan 05, 2025

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 27 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. 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: 9241277, 11499719, 21302287, 21959974, 30550750). This variant is also known as IVS27 +1G>A. ClinVar contains an entry for this variant (Variation ID: 42666). Studies have shown that disruption of this splice site results in skipping of exon 27, but is expected to preserve the integrity of the reading-frame (PMID: 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic. -

Aug 23, 2024

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 27 of the MYBPC3 gene. Functional RNA studies have shown that this variant causes in-frame skipping of exon 27, resulting in creation of a stop codon at the junction of exons 26 and 28 and a significant reduction of mutant mRNA transcript in heart tissue and cell lines from individuals carrying this variant (PMID: 11499719, 25031304, 27620334). This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 11499719, 21302287, 21959974, 23396983, 27532257, 32815737, 33673806, 38002985). 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. -

Hypertrophic cardiomyopathy 4 Pathogenic:1 Uncertain:1

-

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Mar 10, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042666 /PMID: 9241277 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiomyopathy Pathogenic:1

Jul 11, 2024

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 27 of the MYBPC3 gene. Functional RNA studies have shown that this variant causes in-frame skipping of exon 27, resulting in creation of a stop codon at the junction of exons 26 and 28 and a significant reduction of mutant mRNA transcript in heart tissue and cell lines from individuals carrying this variant (PMID: 11499719, 25031304, 27620334). This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9241277, 11499719, 21302287, 21959974, 23396983, 27532257, 32815737, 33673806, 38002985). 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. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Nov 02, 2020

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.2905+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: Three predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Erdmann_2001). The variant was absent in 199606 control chromosomes. c.2905+1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Kimura_1997, Erdmann_2001, Erdmann_2003, Roncarati_2011, Lopes_2013, , Kapplinger_2014). These data indicate that the variant is very likely to be associated with disease. Seven 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Sep 02, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2905+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 27 of the MYBPC3 gene. This mutation, also referred to as IVS27+1G>A, has been detected numerous times in individuals with hypertrophic cardiomyopathy (HCM) and in HCM cohorts (Kimura A et al. Nat. Genet. 1997;16:379-82; Erdmann J et al. J. Am. Coll. Cardiol. 2001;38:322-30; Roncarati R et al. J. Cell. Physiol. 2011;226:2894-900; Bashyam MD et al. Mol. Cell. Biochem. 2012;360:373-82; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet Med. 2016;epub). Several RNA studies have demonstrated that this mutation causes the skipping of exon 27, creating a transcript with a premature stop codon at the exon 26-exon 28 intersection that undergoes nonsense-mediated decay (Erdmann J et al. J. Am. Coll. Cardiol. 2001;38:322-30; Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Monteiro da Rocha A et al. J. Mol. Cell. Cardiol. 2016;99:197-206). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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 a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.5
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 1

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

Other links and lift over

dbSNP: rs397515991; hg19: chr11-47356592;