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 14 ACMG points: 14P and 0B. PVS1_Moderate PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000208131: 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)" and additional evidence is available in ClinVar.

• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AD, AR 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
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy

  Inheritance: AR, AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000208131: 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).; SCV000280252: 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. (2001) PMID:11733440; SCV000059187: 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).; SCV000253813: RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. PMID:11499719; SCV004814322: 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).; SCV001448363: The variant was 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. Experimental evidence that this variant affects mRNA splicing (Erdmann_2001).; SCV004358657: 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).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.2905+1G>A		splice_donor intron	N/A	NP_000247.2	Q14896-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.2905+1G>A		splice_donor intron	N/A	ENSP00000442795.1	Q14896-1
	MYBPC3	ENST00000399249.6	TSL:5	c.2905+1G>A		splice_donor intron	N/A	ENSP00000382193.2	A8MXZ9

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hypertrophic cardiomyopathy (3)
3	-	-	not provided (3)
1	1	-	Hypertrophic cardiomyopathy 4 (2)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

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;