11-47333189-C-G

Variant names:

• chr11-47333189-C-G
• rs373746463
• NM_000256.3:c.3330+5G>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.3330+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000137 in 1,601,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 5.28
• Publications: 8 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.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 11-47333189-C-G is Pathogenic according to our data. Variant chr11-47333189-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42706.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.3330+5G>C		splice_region_variant, intron_variant	Intron 30 of 34	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3330+5G>C		splice_region_variant, intron_variant	Intron 30 of 34	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.3330+5G>C		splice_region_variant, intron_variant	Intron 29 of 33	5		ENSP00000382193.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 227064 AF XY: 0.0000163

Gnomad AFR exome AF: 0.000293

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1449338 Hom.: 0 Cov.: 34 AF XY: 0.00000695 AC XY: 5 AN XY: 719586

African (AFR) AF: 0.000330 AC: 11 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 43226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39314

South Asian (SAS) AF: 0.00 AC: 0 AN: 83702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106084

Other (OTH) AF: 0.00 AC: 0 AN: 59902

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74336

African (AFR) AF: 0.000266 AC: 11 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000223 Hom.: 0

Bravo AF: 0.0000793

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Sep 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PS3, PS4_moderate, PVS1

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 28, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Splice site variant demonstrated to result in loss-of-function (Watkins et al., 1995); Other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy, including two other nucleotide substitutions at the same intronic position (c.3330+5 G>T, c.3330+5 G>A) (HGMD); This variant is associated with the following publications: (PMID: 24033266, 23782526, 25351510, 29121657, 30550750, 7493025, 23534983, 24704860, 28518168, 26688388, 28679633, 28138913, 29212898, 25611685, 23054336, 31028938, 31447099, 33906374)

Jun 18, 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 IVS30+5 G>C Based on the data reviewed below we consider this variant likely disease-causing. The variant has been reported previously in one family with HCM (Watkins H et al., 1995). 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. . The variant was showed to lead to an aberrant splice transcript due to skipping of exon 30, shift in the reading frame, and premature termination of translation in exon 31. In total the variant has not been seen in ~6,600 published controls and individuals from publicly available population datasets. There is no variation at c.3330+5 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,5000 Caucasian and African American individuals (as of 9/20/13). There are only two individuals reported in this cohort with splice donor variants in MYBPC3. The variant was not observed in the following published control samples: Watkins et al, not present in 100 control individuals.

Jan 12, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hypertrophic cardiomyopathy 4 Pathogenic:5

Jul 25, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYBPC3 c.3330+5G>C variant, also known as IVS30+5G>C, results in the substitution of a guanine with a cytosine within a splice region near a canonical splice donor site. Functional studies have shown that this variant results in the skipping of exon 30, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein (PMID: 7493025; PMID: 28679633). Loss of normal protein function through nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with hypertrophic cardiomyopathy (PMID: 7493025; PMID: 23534983; PMID: 24704860; PMID: 29212898; PMID: 30550750). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been shown to segregate with disease in a multigenerational family (PMID: 7493025). Based on the available evidence, the MYBPC3 c.3330+5G>C variant is classified as pathogenic for hypertrophic cardiomyopathy.

Nov 07, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 06, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PS3, PP1, PP3, PP5

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - 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). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to cause skipping of exon 30, resulting in a frameshift (PMID: 7493025), which is predicted to result in nonsense-mediated decay (NMD). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same splice site, is present in gnomAD (v3; 2 heterozygotes, 0 homozygotes). (SB) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic in ClinVar. In addition, two different nucleotide substitutions at the same splice site, c.3330+5G>T and c.3330+5G>A, have also been reported as pathogenic for HCM in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with HCM (ClinVar, LOVD, PMID: 7493025, 29212898, 24704860, 29625023, 31028938). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has been reported to segregate in a multigenerational family with HCM (PMID: 7493025). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Jan 14, 2020

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Hypertrophic cardiomyopathy Pathogenic:3

Apr 04, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3330+5G>C variant in MYBPC3 has been reported in >12 individuals with HCM and segregated with disease in 8 affected relatives from 3 families (Watkins 1995, Captur 2014, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 7493025) and has been identified in 7/22230 African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org). This variant has been shown to cause skipping of exon 30, resulting in a frameshift and premature stop codon, which is predicted to lead to truncated or absent protein (Watkins 1995). Heterozygous loss of MYBPC3 function is an established disease mechanism in individuals with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon presence in multiple affected individuals, very low frequency in the general population, segregation studies and the predicted impact to the protein. ACMG/AMP Criteria applied (Richards 2015): PS4_moderate, PM2, PP1_Strong, PVS1.

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 30 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 (rs373746463, gnomAD 0.03%). This variant has been observed in individual(s) with familial hypertrophic cardiomyopathy (PMID: 7493025). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42706). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 30, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7493025). For these reasons, this variant has been classified as Pathogenic.

Sep 13, 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 C nucleotide substitution at the +5 position of intron 30 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing, resulting in out-of-frame skipping of exon 30 and premature truncation (PMID: 7493025, 28679633). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493025, 23782526, 24704860, 25611685, 28193612, 29121657, 29212898, 30550750, 35508642, 36704059). It has been shown that this variant segregates with disease in affected families (PMID: 7493025, 24704860, ClinVar SCV000059231.5). This variant has been identified in 7/258400 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 Pathogenic.

Cardiomyopathy Pathogenic:2

May 05, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 24, 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 C nucleotide substitution at the +5 position of intron 30 of the MYBPC3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing, resulting in out-of-frame skipping of exon 30 and premature truncation (PMID: 7493025, 28679633). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493025, 23782526, 24704860, 25611685, 28193612, 29121657, 29212898, 30550750, 35508642, 36704059). It has been shown that this variant segregates with disease in affected families (PMID: 7493025, 24704860, ClinVar SCV000059231.5). This variant has been identified in 7/258400 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 Pathogenic.

Cardiovascular phenotype Pathogenic:2

Jul 18, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 27, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3330+5G>C intronic alteration consists of a G to C substitution 5 nucleotides after coding exon 30 in the MYBPC3 gene. Based on data from gnomAD, the C allele has an overall frequency of 0.003% (7/258400) total alleles studied. The highest observed frequency was 0.031% (7/22340) of African alleles. This variant was reported to cause skipping of exon 30 in lymphocytes from affected individuals and segregated with hypertrophic cardiomyopathy (HCM) in six individuals from three generations in one family (Watkins, 1995). This variant has also been detected in additional unrelated individuals with HCM (Miller, 2013; Alfares, 2015) This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

Left ventricular noncompaction 10 Pathogenic:1

Nov 07, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Oct 19, 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.3330+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site and two predict it weakens a 5' donor site. At least two publications report experimental evidence that this variant affects mRNA splicing (Watkins_1995, Ito_2017). The variant allele was found at a frequency of 1.8e-05 in 227264 control chromosomes (gnomAD and publication). c.3330+5G>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Watkins_1995, Nunez_2013, Captur_2014, Miller_2017), including a large family in which the variant segregated with the disease (Watkins_1995). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

MYBPC3-related disorder Pathogenic:1

May 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MYBPC3 c.3330+5G>C variant is predicted to interfere with splicing. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Watkins et al. 1995. PubMed ID: 7493025; Table S7 - Alfares et al. 2015. PubMed ID: 25611685). In one family, the variant segregated in seven individuals with hypertrophic cardiomyopathy over three generations and was absent in eight unaffected individuals (Watkins et al. 1995. PubMed ID: 7493025). Of note, one unaffected individual was positive for this variant (Watkins et al. 1995. PubMed ID: 7493025). Splicing studies indicate this variant leads to exon skipping, which results in premature protein truncation (Watkins et al. 1995. PubMed ID: 7493025). This variant has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/42706/). Additionally, different variants affecting the same nucleotide (c.3330+5G>A and c.3330+5G>T) have been reported in individuals with hypertrophic cardiomyopathy (Table S7 - Alfares et al. 2015. PubMed ID: 25611685; Table S1 - Wang et al. 2014. PubMed ID: 25132132). This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 39
DS_DL_spliceai		0.30		Position offset: 5

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

Other links and lift over

dbSNP: rs373746463; hg19: chr11-47354740;