VCV000222710.10 - ClinVar

NM_000256.3(MYBPC3):c.3331-2A>C

Germline

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.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.3331-2A>C

Variation ID: 222710 Accession: VCV000222710.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332975 (GRCh38) [ NCBI UCSC ] 11: 47354526 (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	Feb 27, 2016	May 1, 2024	Nov 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3331-2A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000011.10:g.47332975T>G
NC_000011.9:g.47354526T>G
NG_007667.1:g.24728A>C
LRG_386:g.24728A>C
LRG_386t1:c.3331-2A>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:47332974:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA352005 dbSNP: rs869025469 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	3971	3990

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.
Primary familial hypertrophic cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Dec 7, 2015	RCV000208403.1
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 16, 2016	RCV000270014.1
Hypertrophic cardiomyopathy	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 21, 2023	RCV001853310.6
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Jun 24, 2022	RCV002321823.2
Cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Jun 21, 2023	RCV003532053.1

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.	More information 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.
Likely pathogenic (Dec 07, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Primary familial hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000264059.2 First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016	Number of individuals with the variant: 1
Pathogenic (Jun 16, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330210.6 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: Although the c.3331-2 A>C variant has not been reported in the literature as a pathogenic variant or as a benignvariant to our knowledge, it destroys … (more) Although the c.3331-2 A>C variant has not been reported in the literature as a pathogenic variant or as a benignvariant to our knowledge, it destroys the canonical splice acceptor site in intron 30 and is predicted to cause abnormalgene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediatedmRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice sitevariants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014).Furthermore, the c.3331-2 A>C variant was not observed in approximately 6,100 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations.In summary, c.3331-2 A>C in the MYBPC3 gene is interpreted as a pathogenic variant. (less)
Likely pathogenic (Jun 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV004358635.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Comment: This variant causes an A to C nucleotide substitution at the -2 position of intron 30 of the MYBPC3 gene. Splice site prediction tools predict … (more) This variant causes an A to C nucleotide substitution at the -2 position of intron 30 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 2/237500 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.3331-2A>G, c.3331-1G>A and c.3331-1G>C, are known to be disease-causing (ClinVar variation ID: 1878689, 177742 and 519194). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Likely pathogenic (Nov 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002307689.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 16199547‚ 19574547‚ 28640247 Comment: This sequence change affects an acceptor splice site in intron 30 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 30 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28640247). ClinVar contains an entry for this variant (Variation ID: 222710). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. (less)
Likely pathogenic (Jun 24, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002606588.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 27600940‚ 28640247‚ 30297972‚ 33087929 Comment: The c.3331-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 31 in the MYBPC3 gene. Alterations that disrupt … (more) The c.3331-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 31 in the MYBPC3 gene. Alterations 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 may result in the creation or strengthening of a novel splice acceptor site. This variant has been reported in at least two individuals with hypertrophic cardiomyopathy (HCM) (Ambry internal data; Invitae pers. comm.). Additional alterations impacting the same acceptor site (c.3331-2A>G, c.331-1G>A, c.331-1G>C) have been detected in HCM cases (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Ko C et al. Genet Med, 2018 01;20:69-75; Ho CY et al. Circulation, 2018 10;138:1387-1398). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Likely Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004825210.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This variant causes an A to C nucleotide substitution at the -2 position of intron 30 of the MYBPC3 gene. Splice site prediction tools predict … (more) This variant causes an A to C nucleotide substitution at the -2 position of intron 30 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 2/237500 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.3331-2A>G, c.3331-1G>A and c.3331-1G>C, are known to be disease-causing (ClinVar variation ID: 1878689, 177742 and 519194). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. (less) Number of individuals with the variant: 1

Comment:

Although the c.3331-2 A>C variant has not been reported in the literature as a pathogenic variant or as a benignvariant to our knowledge, it destroys the canonical splice acceptor site in intron 30 and is predicted to cause abnormalgene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediatedmRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice sitevariants in the MYBPC3 gene have been reported in HGMD in association with HCM (Stenson et al., 2014).Furthermore, the c.3331-2 A>C variant was not observed in approximately 6,100 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations.In summary, c.3331-2 A>C in the MYBPC3 gene is interpreted as a pathogenic variant.

Comment:

This variant causes an A to C nucleotide substitution at the -2 position of intron 30 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 not been reported in individuals affected with MYBPC3-related disorders in the literature. This variant has been identified in 2/237500 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.3331-2A>G, c.3331-1G>A and c.3331-1G>C, are known to be disease-causing (ClinVar variation ID: 1878689, 177742 and 519194). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

This sequence change affects an acceptor splice site in intron 30 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28640247). ClinVar contains an entry for this variant (Variation ID: 222710). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Comment:

The c.3331-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 31 in the MYBPC3 gene. Alterations 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 may result in the creation or strengthening of a novel splice acceptor site. This variant has been reported in at least two individuals with hypertrophic cardiomyopathy (HCM) (Ambry internal data; Invitae pers. comm.). Additional alterations impacting the same acceptor site (c.3331-2A>G, c.331-1G>A, c.331-1G>C) have been detected in HCM cases (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Ko C et al. Genet Med, 2018 01;20:69-75; Ho CY et al. Circulation, 2018 10;138:1387-1398). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe).	Ho CY	Circulation	2018	PMID: 30297972
Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup.	Ko C	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28640247
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.	Cecconi M	International journal of molecular medicine	2016	PMID: 27600940
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs869025469 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.3331-2A>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs869025469 ...