ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1928-2A>G
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000256.3(MYBPC3):c.1928-2A>G
Variation ID: 42585 Accession: VCV000042585.50
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47339792 (GRCh38) [ NCBI UCSC ] 11: 47361343 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 May 1, 2024 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.1928-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000011.10:g.47339792T>C NC_000011.9:g.47361343T>C NG_007667.1:g.17911A>G LRG_386:g.17911A>G LRG_386t1:c.1928-2A>G - Protein change
- Other names
- MYBPC3, IVS, A-G
- IVS, A-G
- Canonical SPDI
- NC_000011.10:47339791:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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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. |
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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3890 | 3907 |
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. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 6, 2018 | RCV000009136.11 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 23, 2024 | RCV000157326.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV000158133.20 | |
Pathogenic (1) |
criteria provided, single submitter
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May 25, 2023 | RCV000250981.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515302.3 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 26, 2024 | RCV000229899.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 14, 2018 | RCV000779063.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 8, 2023 | RCV001177884.8 |
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. |
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Pathogenic
(Aug 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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MYBPC3-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915529.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MYBPC3 c.1928-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1928-2A>G … (more)
The MYBPC3 c.1928-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1928-2A>G variant has not been observed in individuals with either autosomal dominant dilated cardiomyopathy or left ventricular noncompaction cardiomyopathy. Across a selection of the available literature, the c.1928-2A>G variant has been identified in a heterozygous state in 28 families in which it was found in 82 individuals affected with hypertrophic cardiomyopathy, of whom up to 35 individuals are related, in five individuals with an unknown diagnosis or discrete signs of disease, and in six healthy carriers (Bonne et al. 1995; Charron et al. 1998; Erdmann et al. 2001; Richard et al. 2003; Teirlinck et al. 2012). The c.1928-2A>G variant was shown to segregate with disease in two four-generation French families and in a further 13 families of European origin (Bonne et al. 1995; Richard et al. 2003). One of the studies calculated disease penetrance to be 69% and described the variant as being associated with a mild ventricular hypertrophy (Charron et al. 1998). The c.1928-2A>G variant was absent from 600 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Analysis of MYBPC3 mRNA from patient lymphoblastoid cell lines showed that the c.1928-2A>G variant results in aberrant splicing, causing the skipping of exon 21 and a frameshift with the introduction of a premature stop codon after amino acid residue 661 (Bonne et al. 1995). Expression of the c.1928-2A>G variant in COS-7 cells revealed accumulation to a level similar to wild type, while in fetal rat cardiomyocytes, the variant accumulated to a level that was approximately two-thirds of wild type. Eleven percent of fetal rat cardiomyocyte cells expressing the variant localized correctly in double stripes in the A-band of the sarcomere, but in a more diffuse pattern compared to wild type (Flavigny et al. 1999). Based on the collective evidence and due to the potential impact of splice acceptor variants, the c.1928-2A>G variant is classified as pathogenic for MYBPC3-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987541.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Pathogenic
(Aug 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059101.6
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
The c.1928-2A>G variant in MYBPC3 has been identified in >40 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in >20 affected relatives across several … (more)
The c.1928-2A>G variant in MYBPC3 has been identified in >40 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in >20 affected relatives across several families (Bonne 1995, Charron 1998, Erdmann 2001, Richard 2003, Fokstuen 2008, Millat 2010, Teirlinck 2012, Valente 2013, Kapplinger 2014, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID:42585) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown to lead to aberrant splicing and subsequently a premature stop codon at position 661 (Bonne 1995, Flavigny 1999, Erdmann 2001). Please note that alternate nomenclature was used in some studies (Charron 1998: SAS int20; Richard 2003: IVS21-2A>G; Erdmann 2001: IVS20-2A>G). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3. (less)
Number of individuals with the variant: 53
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Pathogenic
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000208068.14
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; mRNA functional studies have demonstrated this variant leads to aberrant gene splicing and the introduction of a premature stop codon (Bonne et al., 1995; Erdmann et al., 2001; Helms et al., 2014); Multiple other splice site variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (HGMD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42585; ClinVar); This variant is associated with the following publications: (PMID: 25031304, 20439259, 10610770, 28597742, 20624503, 24865491, 12707239, 9503187, 18409188, 23140321, 23348723, 25525159, 25611685, 23690394, 26743238, 26914223, 27532257, 28822653, 28369730, 24510615, 28790153, 25351510, 30128729, 31006259, 30550750, 31447099, 27688314, 31513939, 11499719, 7493026, 31737537, 33954932) (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812852.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in MYBPC3 occurs within the canonical splice acceptor site of intron 20. It is predicted to cause cryptic acceptor activation resulting in … (more)
This sequence change in MYBPC3 occurs within the canonical splice acceptor site of intron 20. It is predicted to cause cryptic acceptor activation resulting in an 11bp deletion in exon 21 leading to premature termination codon and nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. This prediction is confirmed by RT-PCR in patient cells (PMID: 7493026, 25031304). An assay also detected intron 20 inclusion predicting a premature termination codon introduced in intron 20 resulting in the disruption in the production of the MYBPC3 protein (PMID: 25031304). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (PMID: 23140321, 7493026, 12707239, 24510615, 9503187, 11499719, 20439259). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PM2_Supporting. (less)
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Pathogenic
(May 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611208.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Pathogenic
(Feb 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
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Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299246.2
First in ClinVar: Sep 09, 2016 Last updated: Oct 22, 2016 |
Comment:
This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact … (more)
This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to have an impact on protein function according to multiple prediction programs. In addition, the variant has been reported previously in individuals with cardiomyopathy. The c.1928-2 A>G variant affects the canonical splice acceptor site of intron 20 and leads to aberrant gene splicing and the introduction of a premature stop codon (PMID: 11499719; PMID: 7493026; PMID: 25031304). (less)
Sex: female
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, University of Leuven
Accession: SCV000886756.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
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Pathogenic
(Jul 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000897968.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
Age: 40-49 years
Sex: male
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447265.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypertrophic cardiomyopathy (present)
Sex: male
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Pathogenic
(May 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042151.2
First in ClinVar: Jan 01, 2022 Last updated: Mar 11, 2023 |
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Pathogenic
(Jan 26, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000284218.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 20 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 20 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). ClinVar contains an entry for this variant (Variation ID: 42585). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 10610770, 11499719, 25031304). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001342181.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes an A to G nucleotide substitution at the -2 position of intron 20 of the MYBPC3 gene. Splice site prediction tools predict … (more)
This variant causes an A to G nucleotide substitution at the -2 position of intron 20 of the MYBPC3 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have confirmed that this variant causes aberrant splicing and is expected to result in an absent or disrupted protein product (PMID: 11499719, 25031304). This variant has been reported in over 30 individuals affected with hypertrophic cardiomyopathy (PMID: 7493026, 11499719, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615, 28615295). This variant has not been identified 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. (less)
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Pathogenic
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004803668.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
Variant summary: MYBPC3 c.1928-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: MYBPC3 c.1928-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Publications report experimental evidence that this variant affects mRNA splicing (Erdmann_2001, Bonne_1995). The variant was absent in 248758 control chromosomes. c.1928-2A>G has been reported in the literature in numerous individuals and families affected with Hypertrophic Cardiomyopathy (ie. Erdmann_2001, Bonne_1995, Fokstuen_MYH7_2008. ClinVar contains an entry for this variant (Variation ID: 42585). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002821623.8
First in ClinVar: Jan 21, 2023 Last updated: Apr 15, 2024 |
Comment:
MYBPC3: PVS1, PM2
Number of individuals with the variant: 1
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004833560.1
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)
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Comment:
The c.1928-2A>G variant of the MYBPC3 gene is predicted to disrupt the acceptor splice site in intron 20, resulting in abnormal RNA splicing. Variants that … (more)
The c.1928-2A>G variant of the MYBPC3 gene is predicted to disrupt the acceptor splice site in intron 20, resulting in abnormal RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (PMID: 7493026) and has since then been reported in multiple unrelated individuals and families with HCM (PMID: 11499719, 12707239, 18409188, 20439259, 20624503, 23140321, 23690394, 24510615). This variant has been shown to lead to abnormal mRNA splicing and result in loss of protein expression (PMID: 10610770, 11499719, 25031304). This variant is absent in the general population (gnomAD). Based on these evidence, the c.1928-2A>G variant in MYBPC3 is classified as pathogenic. (less)
Number of individuals with the variant: 3
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Pathogenic
(May 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000320293.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The c.1928-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 21 of the MYBPC3 gene. Alterations that disrupt the … (more)
The c.1928-2A>G intronic variant results from an A to G substitution two nucleotides before coding exon 21 of the MYBPC3 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was first reported in two large French kindreds with hypertrophic cardiomyopathy (HCM) (Bonne, 1995), and has since been reported in multiple unrelated individuals and families with HCM (Charron, 1998 (reported as SAS int20); Richard, 2003 (reported as IVS21-2A>G); Teirlinck, 2012 (reported as IVS202A>G); Kapplinger, 2014). This alteration has been shown to lead to abnormal splicing resulting in aberrant protein product (Bonne, 1995; Erdmann, 2001). 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. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Dec 01, 1995)
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no assertion criteria provided
Method: literature only
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CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029353.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 04, 2019 |
Comment on evidence:
In 2 French kindreds with chromosome 11-linked hypertrophic cardiomyopathy (CMH4; 115197), Bonne et al. (1995) found 2 cDNAs of different lengths, 336 bp and 196 … (more)
In 2 French kindreds with chromosome 11-linked hypertrophic cardiomyopathy (CMH4; 115197), Bonne et al. (1995) found 2 cDNAs of different lengths, 336 bp and 196 bp, in affected individuals. Direct sequencing of the 336 nucleotide product gave 2 different sequences; the normal cDNA and a cDNA with an 11-bp deletion between nucleotides 1960 and 1970. Sequencing of the 196-bp product gave a cDNA with a 140-bp deletion between positions 1960 and 2099. Both deletions resulted in a frameshift followed by a premature stop codon. Studies of genomic DNA revealed an A-to-G transition at a 3-prime splice acceptor site in affected individuals. This mutation accounted for both aberrant transcripts since the 140-bp deletion resulted from skipping the exon that spans positions 1060 to 2099, while the 11-bp deletion resulted from the use of a cryptic splice site downstream from the normal splice site that had been inactivated. The A-to-G transition mutation introduced a new NlaIV restriction site which was used to screen affected and unaffected individuals. (less)
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Pathogenic
(Oct 07, 2014)
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no assertion criteria provided
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000207061.2
First in ClinVar: Feb 06, 2015 Last updated: Apr 15, 2023 |
Number of individuals with the variant: 1
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Pathogenic
(Dec 11, 2019)
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no assertion criteria provided
Method: research
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001430861.1
First in ClinVar: Aug 24, 2020 Last updated: Aug 24, 2020 |
Comment:
The MYBPC3 c.1928-2A>G variant has been identified in numerous HCM probands and has been shown to segregate with disease across several reported families (see references). … (more)
The MYBPC3 c.1928-2A>G variant has been identified in numerous HCM probands and has been shown to segregate with disease across several reported families (see references). This variant occurs at the canonical acceptor splice site of intron 20 and leads to aberrant splicing and subsequently a premature stop codon (Bonne G., et al 1995; Flavigny J., et al 1999; Erdmann J., et al 2001; Helms AS, et al., 2010). This variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 9 HCM probands. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 15 HCM probands (PS4), segregated in multiple families (PP1_Strong) and is rare in the general population (PM2), therefore we classify MYBPC3 c.1928A>G as 'Pathogenic'. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
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 |
Genotype-Dependent and -Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy. | Helms AS | Circulation | 2016 | PMID: 27688314 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. | Helms AS | Circulation. Cardiovascular genetics | 2014 | PMID: 25031304 |
Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy. | Su M | International journal of molecular sciences | 2014 | PMID: 24865491 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy. | Valente AM | Circulation. Cardiovascular genetics | 2013 | PMID: 23690394 |
A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death. | Teirlinck CH | BMC medical genetics | 2012 | PMID: 23140321 |
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
Early identification of mutation carriers in familial hypertrophic cardiomyopathy by combined echocardiography and tissue Doppler imaging. | Gandjbakhch E | European heart journal | 2010 | PMID: 20439259 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. | Fokstuen S | Human mutation | 2008 | PMID: 18409188 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. | Erdmann J | Clinical genetics | 2003 | PMID: 12974739 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. | Erdmann J | Journal of the American College of Cardiology | 2001 | PMID: 11499719 |
COOH-terminal truncated cardiac myosin-binding protein C mutants resulting from familial hypertrophic cardiomyopathy mutations exhibit altered expression and/or incorporation in fetal rat cardiomyocytes. | Flavigny J | Journal of molecular biology | 1999 | PMID: 10610770 |
Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes. | Charron P | European heart journal | 1998 | PMID: 9503187 |
Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy. | Bonne G | Nature genetics | 1995 | PMID: 7493026 |
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Text-mined citations for rs397515937 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.