NM_000256.3:c.2905+1G>C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.2905+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000725 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: 7.2e-7 (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:4
• 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 12 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47335041-C-G is Pathogenic according to our data. Variant chr11-47335041-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 42667.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>C		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>C		splice_donor_variant, intron_variant	Intron 27 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2905+1G>C		splice_donor_variant, intron_variant	Intron 26 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1380230 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 677072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00 AC: 0 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: 9.39e-7 AC: 1 AN: 1065178

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Aug 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 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 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: 21302287, 21959974, 30550750). ClinVar contains an entry for this variant (Variation ID: 42667). 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. -

Cardiomyopathy Pathogenic:1

Mar 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>C nucleotide substitution at the canonical +1 position of intron 27 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in at least one individual affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33495597). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice donor site, c.2905+1G>A, is known to be disease-causing (ClinVar variation ID: 42666). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Nov 06, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PS4_supp -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
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;