ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.821+1G>A
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.821+1G>A
Variation ID: 42791 Accession: VCV000042791.65
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47347856 (GRCh38) [ NCBI UCSC ] 11: 47369407 (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 May 29, 2016 Aug 25, 2024 Apr 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.821+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NC_000011.10:g.47347856C>T NC_000011.9:g.47369407C>T NG_007667.1:g.9847G>A LRG_386:g.9847G>A LRG_386t1:c.821+1G>A - Protein change
- Other names
- -
- Canonical SPDI
- NC_000011.10:47347855:C:T
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
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 |
3940 | 3959 |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Jun 2, 2022 | RCV000158313.36 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2023 | RCV000249601.6 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000168401.21 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 6, 2019 | RCV000845451.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 26, 2021 | RCV001375643.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV001176299.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2024 | RCV001807754.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2021 | RCV001787823.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 29, 2022 | RCV002288533.3 | |
MYBPC3-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2022 | RCV004549435.2 |
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
(Jun 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Left ventricular noncompaction 10
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580945.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS3, PM2_SUP, PP1
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Dec 12, 2013)
|
criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059318.5
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Comment:
The c.821+1G>A variant in MYBPC3 has been previously reported in at least 3 indi viduals with HCM and segregated with disease in 7 affected relatives … (more)
The c.821+1G>A variant in MYBPC3 has been previously reported in at least 3 indi viduals with HCM and segregated with disease in 7 affected relatives from 2 fami lies (Nimura 1998, Erdmann 2001, VanDriest 2004). This variant has also been ide ntified by our laboratory in 5 other individuals with HCM and segregated with di sease in 2 affected relatives from one family. Data from large population studi es are insufficient to assess the frequency of this variant in the general popul ation. This variant occurs in the invariant region (+/- 1,2) of the splice conse nsus sequence and has been demonstrated to cause altered splicing (Erdmann 2001) . In summary, this variant meets our criteria to be classified as pathogenic (h ttp://pcpgm.partners.org/LMM) based upon consistency with the established diseas e causing mechanism. (less)
Number of individuals with the variant: 8
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Pathogenic
(Feb 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Primary dilated cardiomyopathy
Affected status: yes
Allele origin:
somatic
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Loeys Lab, Universiteit Antwerpen
Accession: SCV001572571.1
First in ClinVar: Apr 30, 2021 Last updated: Apr 30, 2021 |
Comment:
This sequence change results in a frameshift variant in the MYBPC3 gene resulting in loss-of function and haploinsufficiency, which is a known disease mechanism(PVS1). The … (more)
This sequence change results in a frameshift variant in the MYBPC3 gene resulting in loss-of function and haploinsufficiency, which is a known disease mechanism(PVS1). The variant affects a highly conserved nucleotide in the splice donor consensus sequence, inactivating this donor site. Several prediction programs expect an effect on splicing (PP3) (SpliceSiteFinder-Like; MaxEntScan, NNSPLICE;Human SplicingFinder). The splicing was confirmed by the presence of exon-7 skipping on cDNA from patient lymphocytes. The aberrant cDNA resulted in a frameshift and a premature termination of translation resulting in a large truncated protein (-80%) lacking the MyBP-C motif containing the phosphorylation sites and the titin and myosin binding sites (PMID: 9048664). This variant is present in population databases (GnomAD 5/ 172994). This variant has been reported in the literature in several families with HCM and showed co-seggregation with HCM in three distinct families (PP1strong) (PMID: 9562578; PMID: 11499719; PMID: 15519027; PMID: 12707239). We identified this variant in a DCM patient and a patients with HCM. In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1strong;PP3). (less)
Number of individuals with the variant: 3
Indication for testing: Primary dilated cardiomyopathy
Family history: no
Sex: male
Tissue: blood
Secondary finding: no
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Pathogenic
(Jan 03, 2022)
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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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3billion
Accession: SCV002058286.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more)
Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042791). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000029, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Left ventricular hypertrophy (present)
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Pathogenic
(Dec 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003822820.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 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: SCV001340216.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant (also known as IVS7+1G>A and as Int8DSG+1A) alters the intron 7 canonical splice donor site of the MYBPC3 gene. Functional RNA studies have … (more)
This variant (also known as IVS7+1G>A and as Int8DSG+1A) alters the intron 7 canonical splice donor site of the MYBPC3 gene. Functional RNA studies have shown that this variant causes causes skipping of exon 7, or exons 7 and 8 leading to frameshift and a premature stop codon in exon 9 (PMID: 11499719). This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 21959974, 24510615, 26914223, 27532257, 29121657, 30165862; Color internal data). It has been reported to segregate with disease in multiple affected individuals from two families (PMID: 9562578, 11499719). This variant has also been reported in an infant affected with sudden unexplained death (PMID: 35027292) and in an individual affected with dilated cardiomyopathy (PMID: 35581137). This variant has been identified in 5/172994 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. (less)
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
unknown
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV005045735.1
First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024 |
Comment:
The c.821+1G>A variant in the MYBPC3 gene is located in intron 7 at the canonical donor splice site. It is predicted to result in splice … (more)
The c.821+1G>A variant in the MYBPC3 gene is located in intron 7 at the canonical donor splice site. It is predicted to result in splice donor loss (SpliceAI delta score: 0.87), and disrupted splicing and an aberrant or absent protein product. This variant has been identified in multiple unrelated individuals with hypertrophic cardiomyopathy (PMID: 35176171, 28750076, 33190526, 21959974, 31941943, 12974739, 11499719, 30165862). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 23816408, 7493025, 19574547). Experimental RNA analysis from patient lymphocytes has shown that this variant results in aberrant transcripts due to exon-skipping and frameshift leading to premature stop codon (PMID: 11499719). The variant is reported in ClinVar (ID: 42791). The variant is rare in the general population according to gnomAD (5/172994 chromosomes). Therefore, the c.821+1G>A variant in the MYBPC3 gene has been classified as pathogenic. (less)
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Pathogenic
(Feb 13, 2019)
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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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Blueprint Genetics
Accession: SCV000928225.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
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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: SCV000987536.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Pathogenic
(Jul 06, 2019)
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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: SCV001363104.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MYBPC3 c.821+1G>A 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.821+1G>A 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing leading to two aberrant transcripts with skipping of either exon 7 alone or exons 7 and 8. Both transcripts led to frame shifts and premature stop codons in exon 9 (Erdmann_2001). The variant allele was found at a frequency of 2.9e-05 in 172994 control chromosomes. c.821+1G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Niimura_1998, Erdmann_2001, Murphy_2016, Viswanathan_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: research
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SUDDEN INFANT DEATH SYNDROME
Affected status: yes
Allele origin:
germline
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Robert's Program, Boston Children's Hospital
Accession: SCV002030065.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
We classify this variant as pathogenic using the following ACMG/AMP criteria: PS3, PVS1, PP1, PP5
Clinical Features:
Sudden infant death syndrome (present)
Sex: male
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Pathogenic
(Jun 02, 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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GeneDx
Accession: SCV000208248.10
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Reported in association with HCM, with several individuals presenting with features of HCM before 30 years of age (Niimura et al., 1998; Erdmann et al., … (more)
Reported in association with HCM, with several individuals presenting with features of HCM before 30 years of age (Niimura et al., 1998; Erdmann et al., 2001; Erdmann et al., 2003; Olivotto et al., 2008; Bashyam et al., 2012; Coppini et al., 2014; Kapplinger et al., 2014; Viswanathan et al., 2017; Lu et al., 2018; Marschall et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Reported to destroy canonical splice donor site of intron 7 and lead to two aberrant splice transcripts, resulting in the skipping of either exon 7 alone, or exons 7 and 8; both transcripts result in a frameshift and premature stop codon in exon 9 (Erdmann et al., 2001).; Multiple other splice site variants in the MYBPC3 gene have been reported in HGMD in association with HCM (HGMD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26914223, 28750076, 31737537, 25525159, 25524337, 21959974, 21415409, 18533079, 22267749, 9562578, 12974739, 27532257, 29121657, 30165862, 19574547, 31028938, 15519027, 11499718, 32344918, 33190526, 26582918, 24510615, 11499719) (less)
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Pathogenic
(Feb 28, 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: SCV000320164.7
First in ClinVar: Oct 02, 2016 Last updated: Apr 15, 2023 |
Comment:
The c.821+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the MYBPC3 gene. This alteration has … (more)
The c.821+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the MYBPC3 gene. This alteration has been reported in multiple families with hypertrophic cardiomyopathy (HCM) and segregated with disease (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Erdmann J et al. J Am Coll Cardiol. 2001;38(2):322-30). This alteration was also observed in HCM testing cohorts; however, clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). In one study, mRNA analysis showed this alteration led to skipping of either exon 7 alone or exons 7 and 8, and both abnormal transcripts resulted in frameshifts and premature stop codons in exon 9 (Erdmann J et al. J Am Coll Cardiol. 2001;38(2):322-30). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical and functional data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. (less)
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Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Heidelberg University
Accession: SCV003936055.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
Sex: male
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Pathogenic
(Sep 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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MYBPC3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004121637.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MYBPC3 c.821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in multiple patients with … (more)
The MYBPC3 c.821+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in multiple patients with hypertrophic cardiomyopathy (Niimura et al. 1998. PubMed ID: 9562578; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Lu et al. 2018. PubMed ID: 30165862; O'Hare et al. 2020. PubMed ID: 33190526). mRNA studies in patients’ lymphocytes confirmed the aberrant splicing (Erdmann et al. 2001. PubMed ID: 11499719). This variant is reported in 0.0081% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-47369407-C-T). Variants that disrupt the consensus splice donor site in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Jun 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042230.3
First in ClinVar: Dec 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 31, 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: SCV000219094.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 7 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 7 of the MYBPC3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397516073, gnomAD 0.009%). Disruption of this splice site has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 15519027, 26914223). It has also been observed to segregate with disease in related individuals. This variant is also known as Int8DSG+1A and IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 42791). Studies have shown that disruption of this splice site results in skipping of exon 7 alone or skipping of exons 7 and 8 and introduces a premature termination codon (PMID: 11499719). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV004811998.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1
Number of individuals with the variant: 1
|
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Pathogenic
(Dec 18, 2023)
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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
|
All of Us Research Program, National Institutes of Health
Accession: SCV004834333.1
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:
This variant (also known as IVS7+1G>A and as Int8DSG+1A) alters the intron 7 canonical splice donor site of the MYBPC3 gene. Functional RNA studies have … (more)
This variant (also known as IVS7+1G>A and as Int8DSG+1A) alters the intron 7 canonical splice donor site of the MYBPC3 gene. Functional RNA studies have shown that this variant causes causes skipping of exon 7, or exons 7 and 8 leading to frameshift and a premature stop codon in exon 9 (PMID: 11499719). This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 11499718, 11499719, 21959974, 24510615, 26914223, 27532257, 29121657, 30165862; Color internal data). It has been reported to segregate with disease in multiple affected individuals from two families (PMID: 9562578, 11499719). This variant has also been reported in an infant affected with sudden unexplained death (PMID: 35027292) and in an individual affected with dilated cardiomyopathy (PMID: 35581137). This variant has been identified in 5/172994 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. (less)
Number of individuals with the variant: 1
|
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Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196746.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
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Pathogenic
(Feb 01, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001334456.23
First in ClinVar: Jun 08, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
|
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Likely pathogenic
(Jan 03, 2012)
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no assertion criteria provided
Method: clinical testing
|
Not provided
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280281.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
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 … (more)
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 IVS7+1G>A This variant has been seen in at least three presumably unrelated cases of HCM. Segregation of the variant with the disease within families suggests identical descent. Erdmann et al (2001) reported the variant in 2 apparently unrelated patients of European descent. It was identified in the first patient, a male whose age of onset was 38, and then was discovered in his two brothers, who had severe disease manifestations before the ages of 30. The variant was also found in their mother, who started exhibiting symptoms at age 59 but whose phenotype was less severe than her sons. The other patient who was a male, presented with HCM at the age of 24 with severe hypertrophy, angina pectoris and dyspnea and died suddenly at the age of 54. This splicing variant led to 2 aberrant RNA transcripts which skipped either exon 7 or both exon 7 and 8. Both transcripts led to frame shifts and premature stop codons on exon 9. (Erdmann et al., 2001) Haplotype analysis across the MYBPC3 locus in the relevant families revealed that all of the individuals who carried this same variant also shared either a disease-associated haplotype or a haplotype that was assumed to be disease- associated, suggesting descent from a common ancestor. (Erdmann et al., 2001) (less)
Number of individuals with the variant: 4
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971587.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001924163.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951321.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy. | Boen HM | The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation | 2022 | PMID: 35581137 |
Genetic Determinants of Sudden Unexpected Death in Pediatrics. | Koh HY | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35027292 |
Adopting High-Resolution Allele Frequencies Substantially Expedites Variant Interpretation in Genetic Diagnostic Laboratories. | Ghani M | The Journal of molecular diagnostics : JMD | 2019 | PMID: 31028938 |
Molecular analysis of inherited cardiomyopathy using next generation semiconductor sequencing technologies. | Lu C | Journal of translational medicine | 2018 | PMID: 30165862 |
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
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 |
Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. | Murphy SL | Journal of cardiovascular translational research | 2016 | PMID: 26914223 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. | Bashyam MD | Molecular and cellular biochemistry | 2012 | PMID: 21959974 |
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15519027 |
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 |
Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. | Maron BJ | Journal of the American College of Cardiology | 2001 | PMID: 11499718 |
Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. | Niimura H | The New England journal of medicine | 1998 | PMID: 9562578 |
Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. | Carrier L | Circulation research | 1997 | PMID: 9048664 |
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Text-mined citations for rs397516073 ...
HelpRecord last updated Aug 25, 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.