ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1800delA
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.1800delA
Variation ID: 42568 Accession: VCV000042568.31
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47341235 (GRCh38) [ NCBI UCSC ] 11: 47362786 (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 Sep 16, 2024 Jul 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.1800delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47341237del NC_000011.9:g.47362788del NG_007667.1:g.16468del LRG_386:g.16468del LRG_386t1:c.1800del LRG_386p1:p.Lys600fs - Protein change
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- Other names
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- Canonical SPDI
- NC_000011.10:47341234:TTT:TT
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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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- Links
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 |
3959 | 3978 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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 (4) |
criteria provided, single submitter
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Jul 10, 2024 | RCV000158353.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 16, 2021 | RCV000585656.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 7, 2023 | RCV000620475.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000628851.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 15, 2023 | RCV001798082.3 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
(Dec 04, 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: SCV000059083.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Lys600fs variant in MYBPC3 has been identified by our laboratory in 2 adul ts with HCM. This frameshift variant is predicted to alter the … (more)
The p.Lys600fs variant in MYBPC3 has been identified by our laboratory in 2 adul ts with HCM. This frameshift variant is predicted to alter the protein?s amino a cid sequence beginning at position 600 and lead to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a trunca ted or absent protein. Heterozygous loss of function of the MYBPC3 gene is an es tablished disease mechanism in HCM patients. In summary, this variant meets crit eria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon c onsistency with the established disease causing mechanism. (less)
Number of individuals with the variant: 4
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Pathogenic
(Jul 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002548735.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Comment:
The inherited c.1800del (p.Lys600AsnfsTer2) variant identified in the MYBPC3 gene is the deletion of a single nucleotide resulting in a frameshift at amino acid 600/1275 … (more)
The inherited c.1800del (p.Lys600AsnfsTer2) variant identified in the MYBPC3 gene is the deletion of a single nucleotide resulting in a frameshift at amino acid 600/1275 (exon 19/35) and is predicted to lead to the premature termination of the protein 2 amino acids downstream. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. Loss-of-function variants in MYBPC3 are known to be pathogenic [PMID: 19574547]. The c.1800del (p.Lys600AsnfsTer2) variant is reported in ClinVar as Pathogenic by multiple submitters (VarID: 42568) and has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature [PMID: 12707239, 20433692, 22857948, 27532257, 20738943]. Given this variant is predicted to lead to the premature termination of the protein, its presence in affected individuals in the literature, and absence in population databases, the c.1800del (p.Lys600AsnfsTer2) variant identified in the MYBPC3 gene is reported as Pathogenic. (less)
Clinical Features:
Intellectual disability (present) , Autism (present) , Delayed speech and language development (present)
Secondary finding: yes
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Pathogenic
(Mar 15, 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
Accession: SCV002042143.2
First in ClinVar: Dec 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000749758.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys600Asnfs*2) 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.Lys600Asnfs*2) 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). This variant is present in population databases (rs397515926, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 20433692, 22857948, 27532257). ClinVar contains an entry for this variant (Variation ID: 42568). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 10, 2024)
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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: SCV000208288.17
First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024 |
Comment:
Identified in multiple unrelated patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 12707239, 22857948, 27532257); Frameshift variant predicted to … (more)
Identified in multiple unrelated patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 12707239, 22857948, 27532257); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22857948, 27153395, 27532257, 31589614, 37652022, 20433692, 20738943, 12707239, 37317833) (less)
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Pathogenic
(Aug 14, 2017)
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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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Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000693459.2
First in ClinVar: Mar 04, 2018 Last updated: Dec 11, 2022 |
Age: 50-59 years
Sex: male
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Pathogenic
(Jun 07, 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: SCV000739948.5
First in ClinVar: Apr 14, 2018 Last updated: Jul 08, 2023 |
Comment:
The c.1800delA pathogenic mutation, located in coding exon 19 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1800, causing … (more)
The c.1800delA pathogenic mutation, located in coding exon 19 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 1800, causing a translational frameshift with a predicted alternate stop codon (p.K600Nfs*2). This alteration (also known as g.12413delA) was reported in two individuals with hypertrophic cardiomyopathy (Richard P et al. Circulation 2003; 107(17):2227-32; Brito D et al. Rev Port Cardiol 2012; 31(9):577-87). 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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Pathogenic
(Apr 10, 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
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All of Us Research Program, National Institutes of Health
Accession: SCV004816475.1
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 deletes 1 nucleotide in exon 19 of the Ig-like domain C4 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. … (more)
This variant deletes 1 nucleotide in exon 19 of the Ig-like domain C4 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 20433692, 20738943, 22857948, 27532257, 33495597). This variant has been identified in 1/203524 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
(-)
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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: SCV001969865.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Apr 07, 2014)
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no assertion criteria provided
Method: clinical testing
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Not provided
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280223.1
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. p.Lys600AsnfsX2 (p.K600NfsX2, p.K600Nfs, p.Lys600Nfs c.1800delA) in exon 19 of the MYBPC3 gene (NM_000256.3). Given that frameshift variants in this gene are a common cause of HCM and that there is strong case and segregation data, we consider this variant very likely disease causing. The variant has been seen in at least 11 unrelated cases of (not including this patient's family). Richard et al (2003) reported the variant in one of 197 unrelated HCM patients from their French cohort. Most were of European ancestry. They analyzed 9 sarcomere genes. Note they refer to the variant as del A 12413 (I found multiple sources that map this as the same variant as p.Lys600AsnfsX2). No segregation data was provided. Brito et al (2012) observed the variant in one of 77 HCM patients from their Portuguese cohort that underwent analysis of 5 sarcomere genes. They note that segregation analysis was performed but don't give specific data for this variant. I found a Spanish publication that appears to be about preimplantation genetic diagnosis for this variant (Vendrell et al 2009). Rodriguez-Garcia et al (2010) reported the variant in two brothers with HCM from their Spanish cohort of 130 HCM patients. They only analyzed MYBPC3 in this study. The same group included a patient with this variant in a paper on conduction system disease in HCM (Barriales-Villa et al 2010). Unfortunately insufficient case details are available to determine if it is the same patient described in the other report. This group also published a very interesting family with a father and daughter with HCM and this variant and mother and son with hypertrabeculation (Ortiz et al 2009). The son did not carry the variant and presumably inherited hypertrabeculation from his mother. Interestingly, the authors note that they have a total of 8 families with HCM and this variant with 21 carriers and 90% penetrance by 30 years of age (also reported in a poster, Ortiz et al, http://spo.escardio.org/eslides/view.aspx?eevtid=33&fp=3253). There were three different families with three affected members with the variant, including one set of three first cousins. It is in ClinVar with a submission from LMM, classifying it as pathogenic, but not including internal case data (SCV000059083). Michels et al (2011) observed the variant in 1 of 327 unrelated Dutch HCM patients. No individual ancestry or phenotype data was reported. They only analyzed MYBPC3. This is a frame-shifting variant that creates a premature stop codon 2 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012).. In total the variant has not been seen in ~6800 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 15th, 2014). Note that this dataset does not match the patient's ancestry (Hispanic). The variant is listed in dbSNP (rs397515926), however the only submission is from LMMM. The variant was not observed in the following published control samples: 100 healthy adults (Richard et al 2003), 200 controls (Rodriguez-Garcia et al 2010). (less)
Number of individuals with the variant: 12
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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: SCV001955754.1 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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Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
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 |
Sarcomeric hypertrophic cardiomyopathy: genetic profile in a Portuguese population. | Brito D | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2012 | PMID: 22857948 |
Severe cardiac conduction disturbances and pacemaker implantation in patients with hypertrophic cardiomyopathy. | Barriales-Villa R | Revista espanola de cardiologia | 2010 | PMID: 20738943 |
Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy. | Rodríguez-García MI | BMC medical genetics | 2010 | PMID: 20433692 |
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
Text-mined citations for rs397515926 ...
HelpRecord last updated Oct 08, 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.