ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1999_2000delinsG (p.Leu667fs)
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.1999_2000delinsG (p.Leu667fs)
Variation ID: 164091 Accession: VCV000164091.15
- Type and length
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Indel, 2 bp
- Location
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Cytogenetic: 11p11.2 11: 47339718-47339719 (GRCh38) [ NCBI UCSC ] 11: 47361269-47361270 (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 May 1, 2024 Jul 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.1999_2000delCTinsG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47339718_47339719delinsC NC_000011.9:g.47361269_47361270delinsC NG_007667.1:g.17984_17985delinsG LRG_386:g.17984_17985delinsG LRG_386t1:c.1999_2000delinsG LRG_386p1:p.Leu667fs - Protein change
- Other names
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- Canonical SPDI
- NC_000011.10:47339717:AG:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
3890 | 3907 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2023 | RCV000811791.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2022 | RCV000158357.6 | |
Pathogenic (1) |
criteria provided, single submitter
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May 5, 2020 | RCV001257483.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 8, 2022 | RCV002415640.2 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2022 | RCV002498696.2 |
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
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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
(Nov 08, 2013)
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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: SCV000198871.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
The Leu667fs variant in MYBPC3 has been identified by our laboratory in 2 Hispan ic individuals with HCM. Data from large population studies is insufficient … (more)
The Leu667fs variant in MYBPC3 has been identified by our laboratory in 2 Hispan ic individuals with HCM. Data from large population studies is insufficient to a ssess the frequency of this variant. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 667 and lead to a pre mature termination codon 15 amino acids downstream. This alteration is then pred icted 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 (http:/ /pcpgm.partners.org/LMM) based on the predicated impact of the variant. (less)
Number of individuals with the variant: 3
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Pathogenic
(May 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
germline
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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001434290.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
This variant leads to a translational frameshift and the introduction of a premature termination codon 15 residues downstream. The variant transcript is predicted to be … (more)
This variant leads to a translational frameshift and the introduction of a premature termination codon 15 residues downstream. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of MYBPC3 is a well-established mechanism of disease for hypertrophic cardiomyopathy (Marston 2009). This variant has been reported in the literature in multiple individuals with hypertrophic or dilated cardiomyopathy (Zimmerman 2010, Bos 2014, Walsh 2017). This variant has an overall allele frequency of 0.00004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PVS1 (less)
Indication for testing: Family history of breast and ovarian cancer
Secondary finding: yes
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Pathogenic
(Oct 12, 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: SCV000208292.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 164091; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20474083, 24793961, 27532257, 27535533) (less)
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Likely pathogenic
(Jan 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV003925257.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
The c.1999_2000delCTinsG (p.Leu667AspfsTer15) variant identified in the MYBPC3 gene resulting in a frameshift at amino acid 667/1275 (exon 21/35) is predicted to lead to the … (more)
The c.1999_2000delCTinsG (p.Leu667AspfsTer15) variant identified in the MYBPC3 gene resulting in a frameshift at amino acid 667/1275 (exon 21/35) is predicted to lead to the premature termination of the protein 15 amino acids downstream and is expected to result in either an abnormal, truncated protein product or loss of protein through nonsense-mediated mRNA decay. The variant has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature (PMID: 20474083, 24793961, 27532257). The variant has 0.0001117 allele frequency in the gnomAD (v3.1.2) database (17 out of 152182 heterozygous alleles, no homozygotes). The variant is reported as Pathogenic by multiple submitters in ClinVar (Variation ID: 164091). Based on the available evidence, the heterozygous c.1999_2000delCTinsG (p.Leu667AspfsTer15) variant identified in the MYBPC3 gene is reported as Likely Pathogenic. (less)
Clinical Features:
Atrial fibrillation (present) , Hypertrophic cardiomyopathy (present)
Secondary finding: no
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Pathogenic
(Jul 19, 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: SCV000952077.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hypertrophic or dilated cardiomyopathy … (more)
For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with hypertrophic or dilated cardiomyopathy (PMID: 20474083, 24793961, 27532257). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change creates a premature translational stop signal (p.Leu667Aspfs*15) 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). (less)
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Pathogenic
(Jul 08, 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: SCV002721769.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.1999_2000delCTinsG pathogenic mutation, located in coding exon 21 of the MYBPC3 gene, results from the deletion of two nucleotides and insertion of one nucleotide … (more)
The c.1999_2000delCTinsG pathogenic mutation, located in coding exon 21 of the MYBPC3 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.L667Dfs*15). This alteration has been reported in subjects with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) (Zimmerman RS et al. Genet. Med., 2010 May;12:268-78; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Walsh R et al. Genet. Med., 2017 02;19:192-203). 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)
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Likely pathogenic
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813836.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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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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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 |
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
A novel custom resequencing array for dilated cardiomyopathy. | Zimmerman RS | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20474083 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Text-mined citations for rs727503192 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.