VCV003377189.2 - ClinVar

NM_000256.3(MYBPC3):c.2309-1G>A

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Pathogenic (1); Uncertain significance (1)

2 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.2309-1G>A

Variation ID: 3377189 Accession: VCV003377189.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47337795 (GRCh38) [ NCBI UCSC ] 11: 47359346 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 25, 2024	Jul 19, 2026	May 12, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2309-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000011.10:g.47337795C>T
NC_000011.9:g.47359346C>T
NG_007667.1:g.19908G>A
LRG_386:g.19908G>A
LRG_386t1:c.2309-1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:47337794:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYBPC3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4727	4749

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hypertrophic cardiomyopathy 4	Pathogenic (1)	criteria provided, single submitter	Oct 10, 2024	RCV004789780.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	May 12, 2026	RCV006714419.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 10, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV005400442.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 21896538‚ 27532257‚ 32841044 Comment: show 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 and 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) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Another splice site variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. c.2309-2A>G has been reported in many affected individuals with HCM (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in seven unrelated individuals (PMIDs: 27532257, 21896538). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (May 12, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV007619069.1 First in ClinVar: Jul 19, 2026 Last updated: Jul 19, 2026	Publications: PubMed (2) PubMed: 21896538‚ 27532257 Comment: show The c.2309-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 24 of the MYBPC3 gene. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy or other cardiomyopathies (Garcia-Pavia P et al. Eur J Heart Fail, 2011 Nov;13:1193-201; Walsh R et al. Genet Med, 2017 Feb;19:192-203). Other variant(s) impacting the same acceptor site (c.2309-2A>G) have been identified in individual(s) with features consistent with hypertrophic cardiomyopathy (Van Driest SL, J. Am. Coll. Cardiol. 2004 Nov; 44(9):1903-10; Roncarati R, J. Cell. Physiol. 2011 Nov; 226(11):2894-900; Lopes LR, Heart 2015 Feb; 101(4):294-301; Rubattu S et al. Int J Mol Sci. 2016;17(8); Walsh R et al Genet Med. 2017;19(2):192-203; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). Variants that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. A resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; although, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

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 and 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) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0703 - Another splice site variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. c.2309-2A>G has been reported in many affected individuals with HCM (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in seven unrelated individuals (PMIDs: 27532257, 21896538). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The c.2309-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 24 of the MYBPC3 gene. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy or other cardiomyopathies (Garcia-Pavia P et al. Eur J Heart Fail, 2011 Nov;13:1193-201; Walsh R et al. Genet Med, 2017 Feb;19:192-203). Other variant(s) impacting the same acceptor site (c.2309-2A>G) have been identified in individual(s) with features consistent with hypertrophic cardiomyopathy (Van Driest SL, J. Am. Coll. Cardiol. 2004 Nov; 44(9):1903-10; Roncarati R, J. Cell. Physiol. 2011 Nov; 226(11):2894-900; Lopes LR, Heart 2015 Feb; 101(4):294-301; Rubattu S et al. Int J Mol Sci. 2016;17(8); Walsh R et al Genet Med. 2017;19(2):192-203; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). Variants that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. A resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; although, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.	Helms AS	Circulation. Genomic and precision medicine	2020	PMID: 32841044
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Genetic basis of end-stage hypertrophic cardiomyopathy.	Garcia-Pavia P	European journal of heart failure	2011	PMID: 21896538

Text-mined citations for this variant ...

Record last updated Jul 27, 2026