ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3372C>A (p.Cys1124Ter)
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.3372C>A (p.Cys1124Ter)
Variation ID: 177701 Accession: VCV000177701.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332932 (GRCh38) [ NCBI UCSC ] 11: 47354483 (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 Jan 31, 2015 Apr 20, 2024 Sep 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3372C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Cys1124Ter nonsense NC_000011.10:g.47332932G>T NC_000011.9:g.47354483G>T NG_007667.1:g.24771C>A LRG_386:g.24771C>A LRG_386t1:c.3372C>A LRG_386p1:p.Cys1124Ter - Protein change
- C1124*
- Other names
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- Canonical SPDI
- NC_000011.10:47332931:G: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.
Exome Aggregation Consortium (ExAC) 0.00002
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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
3858 | 3875 |
Conditions - Germline
Condition
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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
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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 (1) |
criteria provided, single submitter
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Nov 30, 2017 | RCV000413211.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 13, 2021 | RCV000619606.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2021 | RCV000769308.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 30, 2023 | RCV000808027.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2023 | RCV003226219.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2023 | RCV003333033.1 |
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. |
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Pathogenic
(Nov 30, 2017)
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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: SCV000490642.2
First in ClinVar: Jan 09, 2017 Last updated: Apr 17, 2019 |
Comment:
The C1124X variant in the MYBPC3 gene has been reported in association with HCM (Van Driest et al., 2004;Bashyam et al., 2012). Bashyam et al. … (more)
The C1124X variant in the MYBPC3 gene has been reported in association with HCM (Van Driest et al., 2004;Bashyam et al., 2012). Bashyam et al. (2012) describe an Indian boy with HCM at 3-years-old, though hisheterozygous mother and sibling remained asymptomatic. The C1124X variant is predicted to cause loss of normalprotein function either by protein truncation or nonsense-mediated mRNA decay. Other downstream nonsense variantsin the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stensonet al., 2014), indicating that loss of function is a known disease mechanism. Furthermore, this variant is not observedin large population cohorts (Lek et al., 2016). (less)
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Pathogenic
(Sep 13, 2021)
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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: SCV000740242.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.C1124* pathogenic mutation (also known as c.3372C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at … (more)
The p.C1124* pathogenic mutation (also known as c.3372C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3372. This changes the amino acid from a cysteine to a stop codon within coding exon 31. This alteration has been reported in patients with hypertrophic cardiomyopathy (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Bashyam MD et al. Mol Cell Biochem, 2012 Jan;360:373-82; Ko C et al. Genet Med, 2018 01;20:69-75; O'Leary TS et al. J Mol Cell Cardiol, 2019 02;127:165-173). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 14, 2021)
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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
Study: Canadian Open Genetics Repository
Accession: SCV000900686.2 First in ClinVar: May 06, 2019 Last updated: Mar 11, 2023 |
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Pathogenic
(Mar 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041550.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Mar 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041420.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Sep 30, 2023)
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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: SCV000948111.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Cys1124*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Cys1124*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 177701). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 23, 2022)
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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: SCV000203961.5
First in ClinVar: Jan 31, 2015 Last updated: Apr 20, 2024 |
Comment:
The p.Cys1124X variant in MYBPC3 has been reported in 1 individual with HCM (Van Driest 2004 PMID: 15519027). This variant was absent from large population … (more)
The p.Cys1124X variant in MYBPC3 has been reported in 1 individual with HCM (Van Driest 2004 PMID: 15519027). This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1124, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy (http://pcpgm.partners.org/LMM) based on the predicted impact of the variant. ACMG/AMP criteria applied: PVS1, PM2_P. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003922056.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
A Heterozygous Nonsense variant c.3372C>A in Exon 31 of the MYBPC3 gene that results in the amino acid substitution p.Cys1124* was identified. The observed variant … (more)
A Heterozygous Nonsense variant c.3372C>A in Exon 31 of the MYBPC3 gene that results in the amino acid substitution p.Cys1124* was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 177701]. The observed variant has bene previously reported in patients affected with familial hypertrophic cardiomyopathy (Bashyam, Murali D et al., 2012). For these reasons, this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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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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MYBPC3 truncation mutations enhance actomyosin contractile mechanics in human hypertrophic cardiomyopathy. | O'Leary TS | Journal of molecular and cellular cardiology | 2019 | PMID: 30550750 |
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 |
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 |
A low prevalence of MYH7/MYBPC3 mutations among familial hypertrophic cardiomyopathy patients in India. | Bashyam MD | Molecular and cellular biochemistry | 2012 | PMID: 21959974 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15519027 |
Text-mined citations for rs727504289 ...
HelpRecord last updated Apr 20, 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.