11-47343281-C-T

Variant names:

• chr11-47343281-C-T
• rs587776699
• NM_000256.3:c.1224-19G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_000256.3(MYBPC3):​c.1224-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,549,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:3
• Conservation: PhyloP100: 1.45
• Publications: 10 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: Uncertain_significance. The variant received 3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-47343281-C-T is Pathogenic according to our data. Variant chr11-47343281-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138326.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.1224-19G>A		intron	N/A	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.1224-19G>A		intron	N/A	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.1224-19G>A		intron	N/A	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.1224-19G>A		intron	N/A	ENSP00000444259.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000256 AC: 5 AN: 195212 AF XY: 0.0000285

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000859 AC: 12 AN: 1397346 Hom.: 0 Cov.: 40 AF XY: 0.0000116 AC XY: 8 AN XY: 689128

African (AFR) AF: 0.00 AC: 0 AN: 32188

American (AMR) AF: 0.00 AC: 0 AN: 39316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39088

South Asian (SAS) AF: 0.000141 AC: 11 AN: 77992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084490

Other (OTH) AF: 0.00 AC: 0 AN: 58104

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00000473 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:4

Apr 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to A nucleotide substitution at the -19 position of intron 13 of the MYBPC3 gene. A functional mRNA study has shown that this variant introduces a novel splice site at -17 position, extending the transcript by 17 nucleotides creating a frameshift and premature translation stop signal and expected to result in an absent or non-functional protein product (PMID: 18337725). This variant has been reported in greater than 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18258667, 18337725, 28797094, 30645170, 35508642) and in one individual suspected of having hypertrophic cardiomyopathy (PMID: 33673806). This variant has been identified in 5/195212 chromosomes 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 Likely Pathogenic.

Apr 12, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.1224-19G>A variant is classified as Likely Pathogenic (PVS1_Moderate, PS4_Moderate, PM2) MYBPC3 c.1224-19G>A is located in intron 13/34. The variant has been reported in at least 10 proband with a clinical presentation of Hypertrophic Cardiomyopathy (PMID#18258667, 18337725, 33673806, 31006259, 34400558) (PS4_Moderate) and is rare in population databases (gnomAD allele frequency = 0.0025%; 5 het) (PM2). The variant has been reported in dbSNP (rs587776699), in the HGMD database as disease causing (CS081936) and is reported as Likely pathogenic by other diagnostic laboratories (ClinVar#138326). RT-PCR studies confirm this variant results in a 17nt extension of exon 14 which results in a premature termination codon in exon 15 of MYBPC3 (PMID#18337725). This paper suggests the variant may result in a weak denovo splice site and it is unclear what fraction of pre-mRNA is incorrectly spliced (PVS1_Moderate).

Sep 08, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in MYBPC3 is an intronic variant located in intron 13. It is predicted (SpliceAI) and observed to create a de novo acceptor site extending exon 14 by 17 bp in an RNA assay that has not been quantified, resulting in a frameshift, likely leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 18337725). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.01% (12/82,810 alleles) in the South Asian population. The prevalence of the variant in individuals with hypertrophic cardiomyopathy (HCM) is significantly increased compared with the prevalence in the population (19 in 11,237 case genotypes vs 12 in 41,405 control genotypes; odds ratio 5.84, 95%CI=2.84-12.04; PMID: 18337725, 35508642, 33673806; gnomAD v4.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PS4_Moderate.

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 13 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs587776699, gnomAD 0.02%). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18258667, 18337725, 30645170, 33673806, 34400558). ClinVar contains an entry for this variant (Variation ID: 138326). Studies have shown that this variant results in extension of the transcript by 17 nucleotides, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 18337725). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

not provided Pathogenic:2 Uncertain:2

May 24, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hypertrophic cardiomyopathy 4 Pathogenic:3

Aug 11, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: Intron variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 18337725). In silico tool predicts the variant to alter splicing and produce an abnormal transcript [Splice AI: 0.81 (>=0.2 moderate evidence for spliceogenicity)]. Intron variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 18337725). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Apr 29, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been demonstrated to result a 17nt extension of the 5' end of exon 14, which creates a premature termination codon and causes a frameshift (PMID: 18337725); Variant is present in gnomAD <0.01 (v4: 13 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (ClinVar, PMID: 18258667, 18337725, 27841901, 28797094, 30645170, 33673806); Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). Additional information: This variant is heterozygous; This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions; however, recessive inheritance results in a more severe early onset phenotype (OMIM); Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044); Inheritance information for this variant is not currently available in this individual.

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Pathogenic:1

Dec 18, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1224-19G>A likely pathogenic variant in the MYBPC3 gene has been reported in association with hypertrophic cardiomyopathy (Waldmuller et al., 2008; Frank-Hansen et al., 2008; Mendes de Almeida et al., 2017). Additionally, functional studies using mRNA analysis demonstrate that this variant creates a splice acceptor site upstream of the canonical splice acceptor site and adds 17 nucleotides to the transcript (Frank-Hansen et al., 2008). This variant is predicted to result in aberrant gene splicing that leads to protein truncation and frameshift (Frank-Hansen et al., 2018). Furthermore, other deep intronic splice site variants in the MYBPC3 gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the c.1224-19 G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, c.1224-19G>A in the MYBPC3 gene is interpreted as a likely pathogenic variant.

Cardiomyopathy Pathogenic:1

Jun 06, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Uncertain:1

Mar 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1224-19G>A intronic variant results from a G to A substitution 19 nucleotides upstream from coding exon 14 in the MYBPC3 gene. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Frank-Hansen R et al. Eur. J. Hum. Genet., 2008 Sep;16:1062-9; Waldm&uuml;ller S et al. Clin Chem, 2008 Apr;54:682-7; Mendes de Almeida R et al. PLoS One, 2017 Aug;12:e0182946; Singer ES et al. Circ Genom Precis Med, 2019 Jan;12:e002368; Field E et al. J Med Genet, 2022 Aug;59:768-775). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Pathogenic	27
DANN	Benign	0.57
PhyloP100		1.4
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -2

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

Other links and lift over

dbSNP: rs587776699; hg19: chr11-47364832;