ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3764CCA[1] (p.Thr1256del)
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.3764CCA[1] (p.Thr1256del)
Variation ID: 42741 Accession: VCV000042741.25
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 11p11.2 11: 47332117-47332119 (GRCh38) [ NCBI UCSC ] 11: 47353668-47353670 (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 Mar 8, 2017 Feb 28, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3764CCA[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Thr1256del inframe deletion NM_000256.3:c.3767_3769del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000256.3:c.3767_3769delCCA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
inframe deletion NC_000011.10:g.47332117TGG[1] NC_000011.9:g.47353668TGG[1] NG_007667.1:g.25581CCA[1] LRG_386:g.25581CCA[1] LRG_386t1:c.3764CCA[1] LRG_386p1:p.Thr1256del - Protein change
- T1256del
- Other names
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- Canonical SPDI
- NC_000011.10:47332116:TGGTGG:TGG
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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
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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
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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 |
3679 | 3696 |
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 9, 2020 | RCV000158408.6 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 31, 2023 | RCV000466712.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2017 | RCV000506954.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2018 | RCV001170944.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 28, 2022 | RCV002362618.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 20, 2021 | RCV002288531.1 |
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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Likely pathogenic
(Oct 09, 2020)
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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: SCV000208343.12
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 42741; Landrum et al., 2016); In-frame deletion of 1 amino acids in a non-repeat … (more)
Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 42741; Landrum et al., 2016); In-frame deletion of 1 amino acids in a non-repeat region; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25524337, 24793961, 27532257, 28193612, 32527005, 31737537) (less)
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Likely pathogenic
(Jul 20, 2021)
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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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MGZ Medical Genetics Center
Accession: SCV002579283.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Likely pathogenic
(Feb 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604329.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
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Likely pathogenic
(Jan 18, 2018)
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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: SCV001333595.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Likely pathogenic
(May 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: SCV000059267.6
First in ClinVar: May 03, 2013 Last updated: Jul 03, 2020 |
Comment:
The p.Thr1256del variant in MYBPC3 has been previously reported in at least 5 individuals with HCM and segregated with disease in at least 6 affected … (more)
The p.Thr1256del variant in MYBPC3 has been previously reported in at least 5 individuals with HCM and segregated with disease in at least 6 affected relatives (including 2 obligate carriers) from 2 families (Bos 2014, Coppini 2014, Walsh 2017, Weissler-Snir 2017, LMM data). It has been reported in ClinVar (Variation ID: 42741), but was absent from large population studies. This variant is a deletion of one amino acid (Thr) at position 1256 and is not predicted to alter the protein reading frame. In summary, although additional studies are required to fully establish its clinical significance, the p.Thr1256del variant is likely pathogenic. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate, PM2. (less)
Number of individuals with the variant: 12
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Likely pathogenic
(Mar 28, 2022)
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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: SCV002625948.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.3767_3769delCCA variant (also known as p.T1256del) is located in coding exon 33 of the MYBPC3 gene. This variant results from an in-frame CCA deletion … (more)
The c.3767_3769delCCA variant (also known as p.T1256del) is located in coding exon 33 of the MYBPC3 gene. This variant results from an in-frame CCA deletion at nucleotide positions 3767 to 3769. This results in the in-frame deletion of a threonine at codon 1256. This variant has been detected in several unrelated individuals with hypertrophic cardiomyopathy (HCM) and in several HCM cohorts, and has also been shown to segregate with disease (Coppini R et al. J. Am. Coll. Cardiol. 2014;64:2589-600; Walsh R et al. Genet. Med. 2016;epub; Weissler-Snir A et al. Circ Cardiovasc Imaging, 2017 Feb;10(2):pii: e005311; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9(Suppl 2):S292-S298; Lombardi M et al. J Clin Med, 2020 Jun;9(6); GeneDx personal communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 31, 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: SCV000546471.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant, c.3767_3769del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Thr1256del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.3767_3769del, results in the deletion of 1 amino acid(s) of the MYBPC3 protein (p.Thr1256del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 42741). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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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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Mitochondrial Energetics and Ca2(+)-Activated ATPase in Obstructive Hypertrophic Cardiomyopathy. | Lombardi M | Journal of clinical medicine | 2020 | PMID: 32527005 |
Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy. | Weissler-Snir A | Circulation. Cardiovascular imaging | 2017 | PMID: 28193612 |
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 |
Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. | Coppini R | Journal of the American College of Cardiology | 2014 | PMID: 25524337 |
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. | Watkins H | Nature genetics | 1995 | PMID: 7493025 |
Text-mined citations for rs397516040 ...
HelpRecord last updated Mar 05, 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.