ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3776del (p.Gln1259fs)
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.3776del (p.Gln1259fs)
Variation ID: 164021 Accession: VCV000164021.26
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47332110 (GRCh38) [ NCBI UCSC ] 11: 47353661 (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 Feb 2, 2015 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.3776delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47332110del NC_000011.9:g.47353661del NG_007667.1:g.25593del LRG_386:g.25593del LRG_386t1:c.3776del LRG_386p1:p.Gln1259fs - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:47332109: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
- | 3696 |
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
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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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Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2023 | RCV000151057.5 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 17, 2019 | RCV000600560.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 17, 2019 | RCV000621300.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2023 | RCV000628841.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2012 | RCV000844679.5 | |
Likely pathogenic (4) |
criteria provided, single submitter
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Dec 8, 2022 | RCV001706003.7 |
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
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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
(Sep 21, 2015)
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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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745024.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Sep 24, 2012)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Left ventricular noncompaction (Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198794.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Gln1259fs variant in MYBPC3 has not been reported in the literature, but has been identified in 3 families with cardiomyopathy tested by our laboratory … (more)
The Gln1259fs variant in MYBPC3 has not been reported in the literature, but has been identified in 3 families with cardiomyopathy tested by our laboratory (Del lefave 2009, LMM unpublished data). In one family, an infant with LVNC and DCM ( likely to be burnt-out HCM) also carried a de novo variant in MYH7, while the af fected mother (LVNC) carried this frameshift variant in isolation (Dellefave 200 9). In a second family, this frameshift variant was observed in isolation in ind ividuals with HCM, though some individuals carried a second likely disease-causi ng variant in MYH7 causing a spectrum of cardiomyopathies to be observed in the family (including HCM, DCM, LVNC, and ARVC; LMM unpublished data). This frameshi ft variant is predicted to alter the protein?s amino acid sequence beginning at position 1259 and lead to a premature termination codon 72 amino acids downstrea m. This alteration is then predicted to lead to a truncated or absent protein. H eterozygous loss of function of the MYBPC3 gene is an established disease mechan ism in HCM patients. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) (less)
Number of individuals with the variant: 9
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Pathogenic
(Jun 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434954.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals … (more)
The c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is predicted to introduce a premature translational termination codon. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 23674513,25611685) or Left ventricular noncompaction (PMID 20031619) and is extremely rare in general population databases. Therefore, this c.3776delA (p.Gln1259Argfs*72) variant in the MYBPC3 gene is classified as pathogenic. (less)
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Pathogenic
(Jan 17, 2019)
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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: SCV000737354.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The c.3776delA pathogenic mutation, located in coding exon 33 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3776. This … (more)
The c.3776delA pathogenic mutation, located in coding exon 33 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 3776. This deletion causes a translational frameshift that ablates the C-terminal 16 amino acids of myosin binding protein-C and replaces them with 72 spurious amino acids, which results in an elongated protein with an altered C-terminal domain (p.Q1259Rfs*72). This alteration was described in a proband with left ventricular non-compaction cardiomyopathy, who also had a de novo missense alteration in the second allele. The proband was reported to have no normal MYBPC3 protein expression and disorganized sarcomere M bands. This alteration was also present in the proband's mildly affected mother who was 28 years old at the time of examination (Dellefave LM et al. Circ Cardiovasc Genet. 2009;2:442-9). In another study, this alteration was detected in an individual with hypertrophic cardiomyopathy and two unaffected family members (Michels M et al. Eur Heart J. 2009;30:2593-8). In addition to the clinical data presented in the literature, this alteration is expected to be deleterious in nature. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Dec 08, 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: SCV000208344.8
First in ClinVar: Feb 24, 2015 Last updated: Nov 11, 2023 |
Comment:
Identified in an infant with LVNC who also harbored a de novo missense variant in the MYBPC3 gene; the c.3776delA variant was subsequently identified in … (more)
Identified in an infant with LVNC who also harbored a de novo missense variant in the MYBPC3 gene; the c.3776delA variant was subsequently identified in the infant's mildly affected mother (Dellefave et al., 2009); Reported as a common pathogenic variant among individuals of Dutch background (Alimohamed et al., 2021); Frameshift variant predicted to result in protein truncation, as the last 16 amino acids are replaced with 71 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20019025, 22115648, 25611685, 27532257, 19666645, 29121657, 33532905, 26582918, 33500567, 33662488, 19808356, 30297972, 30847666, 20031619, 27535533, 23674513) (less)
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Pathogenic
(Mar 22, 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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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000901751.2 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 27, 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: SCV000749748.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1259Argfs*72) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Gln1259Argfs*72) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MYBPC3 protein. This variant is present in population databases (rs727503166, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with left ventricular noncompaction or hypertrophic cardiomyopathy (PMID: 19808356, 20019025, 20031619, 22115648, 25611685, 27532257, 29121657). ClinVar contains an entry for this variant (Variation ID: 164021). This variant disrupts a region of the MYBPC3 protein in which other variant(s) (p.Arg1271*) have been determined to be pathogenic (PMID: 18533079, 23396983, 27532257). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733025.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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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: SCV001922296.1 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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926665.1 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: SCV001958695.1 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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Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). | Ho CY | Circulation | 2018 | PMID: 30297972 |
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 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. | Witjas-Paalberends ER | Cardiovascular research | 2013 | PMID: 23674513 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
Mortality risk of untreated myosin-binding protein C-related hypertrophic cardiomyopathy: insight into the natural history. | Nannenberg EA | Journal of the American College of Cardiology | 2011 | PMID: 22115648 |
The yield of risk stratification for sudden cardiac death in hypertrophic cardiomyopathy myosin-binding protein C gene mutation carriers: focus on predictive screening. | Christiaans I | European heart journal | 2010 | PMID: 20019025 |
Sarcomere mutations in cardiomyopathy with left ventricular hypertrabeculation. | Dellefave LM | Circulation. Cardiovascular genetics | 2009 | PMID: 20031619 |
Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy. | Theis JL | Circulation. Heart failure | 2009 | PMID: 19808356 |
Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers. | Michels M | European heart journal | 2009 | PMID: 19666645 |
Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
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Text-mined citations for rs727503166 ...
HelpRecord last updated Feb 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.