NM_000256.3(MYBPC3):c.3330+5G>C AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Sep 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000223725.16

Allele description [Variation Report for NM_000256.3(MYBPC3):c.3330+5G>C]

NM_000256.3(MYBPC3):c.3330+5G>C

Gene:

MYBPC3:myosin binding protein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.3330+5G>C

HGVS:

NC_000011.10:g.47333189C>G
NG_007667.1:g.24514G>C
NM_000256.3:c.3330+5G>CMANE SELECT
LRG_386t1:c.3330+5G>C
LRG_386:g.24514G>C
NC_000011.9:g.47354740C>G
c.3330+5G>C

Links:

dbSNP: rs373746463

Molecular consequence:

NM_000256.3:c.3330+5G>C - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208166	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 4, 2022)	germline	clinical testing	Citation Link,
SCV000280261	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (Jun 18, 2015)	germline	clinical testing
SCV001807074	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001918982	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001932099	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002501668	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7493025, 28679633, 29212898, 30550750, 29121657, 28518168, 31447099, 25741868
SCV004226846	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 19, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23782526, 24704860, 28679633, 29212898, 33906374, 34400558, 7493025, 25741868
SCV005199309	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

MYBPC3 truncation mutations enhance actomyosin contractile mechanics in human hypertrophic cardiomyopathy.

O'Leary TS, Snyder J, Sadayappan S, Day SM, Previs MJ.

J Mol Cell Cardiol. 2019 Feb;127:165-173. doi: 10.1016/j.yjmcc.2018.12.003. Epub 2018 Dec 11.

PubMed [citation]

PMID:: 30550750
PMCID:: PMC6592272

Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage.

Viswanathan SK, Sanders HK, McNamara JW, Jagadeesan A, Jahangir A, Tajik AJ, Sadayappan S.

PLoS One. 2017;12(11):e0187948. doi: 10.1371/journal.pone.0187948.

PubMed [citation]

PMID:: 29121657
PMCID:: PMC5679632

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000208166.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280261.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		4	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807074.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001918982.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001932099.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002501668.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226846.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

PP1_moderate, PS3, PS4_moderate, PVS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199309.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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