ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln)
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
-
NM_000256.3(MYBPC3):c.1484G>A (p.Arg495Gln)
Variation ID: 164113 Accession: VCV000164113.74
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47342718 (GRCh38) [ NCBI UCSC ] 11: 47364269 (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 Jun 8, 2015 Apr 20, 2024 Jan 30, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000256.3:c.1484G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg495Gln missense NC_000011.10:g.47342718C>T NC_000011.9:g.47364269C>T NG_007667.1:g.14985G>A LRG_386:g.14985G>A LRG_386t1:c.1484G>A LRG_386p1:p.Arg495Gln Q14896:p.Arg495Gln - Protein change
- R495Q
- Other names
- p.(Arg495Gln)
- Canonical SPDI
- NC_000011.10:47342717:C: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.
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00004
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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
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
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
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 30, 2024 | RCV000168090.19 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 9, 2021 | RCV000171824.6 | |
Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 10, 2023 | RCV000201509.12 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Oct 17, 2023 | RCV000223693.38 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jun 14, 2016 | RCV000336189.5 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 9, 2021 | RCV000589860.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763243.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 16, 2023 | RCV001171139.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 21, 2021 | RCV002287371.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2022 | RCV003147345.4 |
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
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Cardiomyopathy, hypertrophic
Affected status: yes
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000054769.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 |
Number of individuals with the variant: 1
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe)
Accession: SCV000256159.1 First in ClinVar: Nov 05, 2015 Last updated: Nov 05, 2015 |
Number of individuals with the variant: 13
|
|
Pathogenic
(Mar 18, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264026.2
First in ClinVar: Feb 27, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Jun 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
MYBPC3-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000372358.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Across a selection of the available literature, the c.1484G>A (p.Arg495Gln) variant has been reported in a heterozygous state in 18 patients with hypertrophic cardiomyopathy, one … (more)
Across a selection of the available literature, the c.1484G>A (p.Arg495Gln) variant has been reported in a heterozygous state in 18 patients with hypertrophic cardiomyopathy, one patient with left ventricular noncompaction cardiomyopathy, two individuals with an indeterminate status, and in a compound heterozygous state in one individual with hypertrophic cardiomyopathy (Niimura et al. 1998; Zeller et al. 2006; Ehlermann et al. 2008; Millat et al. 2010; Antonio et al. 2011; Marsiglia et al. 2013; Helms et al. 2014). The p.Arg495Gln was also found in a heterozygous state in one unaffected individual but was absent from 536 control chromosomes. The variant is reported at a frequency of 0.00001 in the European (Finnish) population of the Exome Aggregation Consortium but this is based on one allele so is presumed to be rare. Helms et al. (2014) demonstrated that heart tissue samples carrying the p.Arg495Gln variant exhibited higher MYBPC3 expression and transcript levels but no increase in protein abundance when compared to control heart tissues. MYBPC3 variants have displayed reduced penetrance and variable expressivity. Based on the collective evidence, the p.Arg495Gln variant is classified as pathogenic for MYBPC3-related disorders. (less)
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Likely pathogenic
(Sep 07, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492795.1
First in ClinVar: Jan 12, 2017 Last updated: Jan 12, 2017 |
|
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Pathogenic
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744850.1 First in ClinVar: Nov 05, 2015 Last updated: Nov 05, 2015 |
|
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Likely pathogenic
(Aug 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000855753.1
First in ClinVar: May 30, 2018 Last updated: May 30, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893879.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(May 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001150174.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(May 02, 2018)
|
criteria provided, single submitter
Method: research
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV001156327.1
First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020 |
Comment:
The MYBPC3 Arg495Gln variant has been described in many HCM probands and has been reported to segregate with disease in several families (see literature). A … (more)
The MYBPC3 Arg495Gln variant has been described in many HCM probands and has been reported to segregate with disease in several families (see literature). A study analysing the transcript and protein levels in two septal myectomy patients carrying the MYBPC3 Arg495Gln variant revealed that not only did the patients exhibit a 2-fold increase in MYBPC3 protein expression but were also found to predominately express the mutant peptide (Helms AS, et al., 2014), which is supportive of the pathogenic role of the variant. The variant is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in 2 HCM probands. One proband was diagnosed after they suffered resuscitated cardiac arrest in childhood, family screening identified an additional 3 affected family members in which the variant segregated (Ross SB, et al., 2017). The second proband does not have a family history of disease (Ingles et al., 2017). Interestingly, different rare variants at this position (Arg495Trp, Arg495Gly) have also been reported in HCM cases, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, PolyPhen2, and MutationTaster predict this variant to have a deleterious effect. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant has been reported in more than 15 HCM probands (PS4), segregates with disease in multiple families (PP1_strong), is rare in the general population (PM2) and in silico tools predict it to be deleterious (PP3), therefore we classify MYBPC3 Arg495Gln as "pathogenic". (less)
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Pathogenic
(Oct 07, 2019)
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criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428773.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
|
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447092.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypertrophic cardiomyopathy (present)
Sex: male
|
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Pathogenic
(Aug 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Primary familial hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696312.3
First in ClinVar: Mar 17, 2018 Last updated: Sep 08, 2021 |
Comment:
Variant summary: The variant, MYBPC3 c.1484G>A (p.Arg495Gln) results in a conservative amino acid change located in the Immunoglobulin-like domain (Immunoglobulin subtype 2) and Immunoglobulin I-set … (more)
Variant summary: The variant, MYBPC3 c.1484G>A (p.Arg495Gln) results in a conservative amino acid change located in the Immunoglobulin-like domain (Immunoglobulin subtype 2) and Immunoglobulin I-set domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 253236 control chromosomes (gnomAD and publications) and has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Helms_2014, Marsiglia_2013, Ng_2013, Lopes_2013, Millat_2010, Morita_2008, VanDriest_2004, Niimura_1998, Viswanathan_2017). In one family, this variant cosegregates with HCM in three affected family members, however, one unaffected family member whose age was above the age of onset carried this variant implying reduced penetrance or later onset (Niimura_1998). Two co-occurrences with other likely pathogenic variants (MYBPC3 p.Tyr1172fs, TNNI3 Arg141Gln) have been reported in two HCM patients, respectively (Millat_2010, Morita_2008). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating the impact of the variant on protein function, does not allow convincing conclusions about the variant effect (Helms_2014). However, myocardial tissue obtained from a human HCM subject that harbors the variant show molecular signatures of aberrant calcium signaling (increased Ca2+/Calmodulin dependent protein kinase II (CaMKII) activation and reduced SERCA2 (Sarcoplasmic/endoplasmic reticulum calcuium ATPase 2) mRNA levels, (Helms_2016). Experimental evidence suggest that mutations causative of HCM in both thick and thin sarcomere filaments may lead to abnormal calcium handling and increase the risk of arrhythmia in HCM (Helms_2016). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(May 01, 2021)
|
criteria provided, single submitter
Method: research
|
Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
unknown
|
Laan Lab, Human Genetics Research Group, University of Tartu
Accession: SCV002538611.1
First in ClinVar: Jul 01, 2022 Last updated: Jul 01, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Non-obstructive azoospermia (present)
Secondary finding: yes
Method: exome sequencing
|
|
Pathogenic
(May 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579905.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
|
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Pathogenic
(Sep 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000739944.4
First in ClinVar: Mar 17, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.R495Q pathogenic mutation (also known as c.1484G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at … (more)
The p.R495Q pathogenic mutation (also known as c.1484G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1484. The arginine at codon 495 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Niimura H et al. N Engl J Med. 1998;338(18):1248-57; Maron BJ et al. Am J Cardiol. 2011;107(4):604-8; Brito D et al. Rev Port Cardiol. 2012;31(9):577-87; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Mattos BP et al. Arq. Bras. Cardiol., 2016 Sep;107:257-265). This variant has also been detected in noncompaction and dilated cardiomyopathy cohorts (van Waning JI et al. J Am Coll Cardiol. 2018 02;71(7):711-722; Sousa A et al. Rev Port Cardiol (Engl Ed). 2019 Feb;38(2):129-139). In addition, alterations affecting the same amino acid (p.R495W (c.1483C>T) and p.R495G (c.1483C>G)) have also been reported in association with HCM (Page SP et al. Circ Cardiovasc Genet. 2012;5(2):156-66; García-Castro M et al. Rev Esp Cardiol. 2009;62(1):48-56). Based on the supporting evidence, p.R495Q is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Oct 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835517.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
Pathogenic
(Oct 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835506.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
Pathogenic
(Jul 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333823.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
|
|
Pathogenic
(Oct 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Left ventricular noncompaction 10
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045792.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Primary dilated cardiomyopathy (present)
|
|
Pathogenic
(Mar 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV004100671.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Number of individuals with the variant: 1
Age: 50-59 years
Sex: male
Ethnicity/Population group: European
|
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Pathogenic
(Oct 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208030.8
First in ClinVar: Feb 24, 2015 Last updated: Nov 25, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; The p.(R495Q) mutant peptide was predominantly expressed compared to wild-type protein in … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; The p.(R495Q) mutant peptide was predominantly expressed compared to wild-type protein in heart tissue specimens from two HCM patients, though the precise correlation to phenotype is yet to be determined (PMID: 25031304); This variant is associated with the following publications: (PMID: 34598319, 31308319, 31006259, 34542152, 15519027, 11499718, 15115610, 16715312, 18403758, 18409188, 18957093, 20031618, 20019025, 20624503, 21415409, 22857948, 23396983, 23861362, 24093860, 21310275, 24510615, 18761664, 18803133, 9562578, 26671970, 27532257, 28166811, 28024942, 28797094, 29447731, 29121657, 29907873, 30871747, 31737537, 30847666, 31447099, 32480058, 33500567, 34540771, 33673806, 27737317, 32746448, 33407484, 33087929, 34400558, 35626289, 35653365, 35535697, 25031304) (less)
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Pathogenic
(Jun 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017657.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000218744.13
First in ClinVar: Mar 29, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 495 of the MYBPC3 protein (p.Arg495Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 495 of the MYBPC3 protein (p.Arg495Gln). This variant is present in population databases (rs200411226, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499718, 20019025, 22857948, 23396983, 24093860). ClinVar contains an entry for this variant (Variation ID: 164113). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg495 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18403758, 19659763, 20624503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001360091.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 495 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces arginine with glutamine at codon 495 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study using a transgenic pig model heterozygous for this variant has shown a phenotype of myocardial fibrosis as well as reduced MYBPC3 expression levels in cardiac fibroblasts (PMID: 36357371). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 11499718, 20019025, 22857948, 23396983, 24093860, 28024942, 28615295, 29121657, 29907873, 32746448, 35626289). This variant has been shown to segregate with hypertrophic cardiomyopathy in three different families (PMID: 9562578, 27737317, 29121657). This variant has been identified in 6/249188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg495Gly and p.Arg495Trp, are well documented pathogenic mutations (Clinvar variation ID: 42537 and 164114), indicating that arginine at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004834616.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 495 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces arginine with glutamine at codon 495 in the Ig-like domain C3 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study using a transgenic pig model heterozygous for this variant has shown a phenotype of myocardial fibrosis as well as reduced MYBPC3 expression levels in cardiac fibroblasts (PMID: 36357371). This variant has been reported in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 11499718, 20019025, 22857948, 23396983, 24093860, 28024942, 28615295, 29121657, 29907873, 32746448, 35626289). This variant has been shown to segregate with hypertrophic cardiomyopathy in three different families (PMID: 9562578, 27737317, 29121657). This variant has been identified in 6/249188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg495Gly and p.Arg495Trp, are well documented pathogenic mutations (Clinvar variation ID: 42537 and 164114), indicating that arginine at this position is important for MYBPC3 protein function. Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 8
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Pathogenic
(Mar 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: SCV000198912.6
First in ClinVar: Jan 30, 2015 Last updated: Apr 20, 2024 |
Comment:
The p.Arg495Gln variant in MYBPC3 has been reported in >20 individuals with HCM and segregated with disease in 5 affected relatives from 3 families (Niimura … (more)
The p.Arg495Gln variant in MYBPC3 has been reported in >20 individuals with HCM and segregated with disease in 5 affected relatives from 3 families (Niimura 1998 PMID: 9562578, Maron 2001 PMID: 11499718, Van Driest 2004 PMID: 15519027, Ehlermann 2008 PMID: 18957093, Fokstuen 2008 PMID: 18409188, Morita 2008 PMID: 18403758, Millat 2010 PMID: 20624503, Fokstuen 2011 PMID: 21239446, Brito 2012 PMID: 22857948, Lopes 2013 PMID: 23396983, Marsiglia 2013 PMID: 24093860, Kapplinger 2014 PMID: 24510615, Walsh 2017 PMID: 27532257, LMM data). However, multiple unaffected relatives from different families also carried this variant, at least 6 of whom were over the age of 50 (Brito 2012 PMID: 22857948, LMM data), suggesting reduced penetrance. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 164113) and has been identified in 0.005% (1/17974) of East Asian chromosomes and 0.004% (5/112974) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies suggest that carriers of this variant exhibit heightened expression of MYBPC3 as compared to controls, leading to an abundance of the mutant protein in cardiac tissue (Helms 2014 PMID: 25031304). However, it is unclear how this would impact cardiac function. Computation tools and conservation analysis are consistent with pathogenicity. In addition, 2 different amino acid changes at this position (p.Arg495Gly and p.Arg495Trp) have been reported in multiple individuals with HCM (Niimura 1998 PMID: 9562578, Maron 2001 PMID: 11499718, García-Castro 2009 PMID: 19150014, Martín 2009 PMID: 18713777, Rodríguez-García 2010 PMID: 20433692, Brito 2012 PMID: 22857948, Coto 2012 PMID: 22765922, Lopes 2013 PMID: 23396983), suggesting that changes at this position are not tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM; however, it should be noted that penetrance may be reduced. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP1_Moderate, PP3, PM5_supporting. (less)
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Pathogenic
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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see cases
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577925.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PS5,PM1,PM2,PM5,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Cardiomyopathy (present) , Interstitial pneumonitis (present)
Age: 0-9 years
Sex: male
Tissue: blood
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Pathogenic
(Jul 01, 2023)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249486.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Comment:
MYBPC3: PS4, PM2, PM5, PP1:Moderate, PP3
Number of individuals with the variant: 9
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Likely pathogenic
(Mar 17, 2015)
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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: SCV000280212.1
First in ClinVar: Jun 03, 2016 Last updated: Jun 03, 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. MYBPC3 p.Arg495Gln We first reviewed the variant in October 2013. We re-reviewed it October 15th, 2015 and found even stronger data in favor of pathogenicity. The variant has been seen in at least 25 unrelated cases of HCM (not including this patient) with some segregation data in one family. ~10 of these cases may be attributable to a Brazilian founder. Niimura et al. (1998, Seidman group) reported this variant in an individual with HCM within a cohort of 16 families. Three affected family members all had the variant as did two individuals with indeterminate phenotype (described by the authors as left ventricular hypertrophy with confounding factors such as hypertension). Same family is also included in a later paper by the same group (Maron B et al. 2001). Van Driest et al (2004) identified this variant in one patient in a cohort of 389 unrelated patients with HCM at Mayo clinic. No information is given on the patient's phenotype. They report no segregation data. Ehlermann (2008) observed this variant in one HCM patient from a cohort of 87 patients with HCM. Mutation carriers exhibited no additional mutations in genes MYH7, TNNT2, TNNI3, ACTC and TPM1. There is no specific reported clinical data on the patient with this variant. Morita et al. (2008) reported this variant in an individual with HCM while looking at a cohort of 84 children with idiopathic cardiac hypertrophy diagnosed before age 15. This individual also carried TNNI3 Arg141Gln (which we classify as likely disease causing) in addition to the MYBPC3 Arg495Gln variant. No segregation data or parental data was included. Individual phenotypic details were not provided (though onset was pediatric in all cases). Frisso et al (2009) report a patient with HCM from their Italian cohort who underwent analysis of 8 sarcomere genes. He was diagnosed at 2 years of age and his father had left ventricular non-compaction and also carried the variant. Kaski et al (2009, McKenna's group) observed this variant in one patient in a cohort of 79 patients diagnosed with HCM at age 13 years or younger from London. They did not give specific data regarding the patient with this variant nor segregation data. This could overlap with a later report from the same group (Captur et al 2014). Marsiglia et al (2013) observed the variant in 10 of 268 unrelated HCM patients from their Brazilian cohort who underwent sequencing of MYH7, MYBPC3, TNNT2. Ackerman's group observed the variant in 7 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases may overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and perhaps also with internal data from genetic testing labs. Sharlene Day's group included two unrelated HCM patients with this variant in a recent paper on transcription levels in MYBPC3 carriers (Helms et al 2014). That case may overlap with internal data from clinical labs. We have seen the variant in one other patient with HCM in our center. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this variant to be disease-causing. The arginine at codon 495 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Arg495Trp, Arg495Gly) and nearby codons (Thr494lle; Gly490Arg). Niimura notes that this variant is in the 244-amino acid segment that spans the phosphorylation domain of the molecule. Helms et al (2014) observed an increase in expression of the mutant peptide in heart tissue of two unrelated HCM patients with this variant. In total the variant has not been seen in ~8,000 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 495 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/15/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/15/13). The variant was not observed in the following laboratory and published control samples: Familion internal control population of over 400 unrelated, ethnically diverse, presumed healthy individuals. Kaski et al did not observe this variant in 200 presumed healthy controls. Morita reports this variant was absent in 180 unrelated persons matched by ancestral origin to the subjects and in more than 1000 chromosomes of unaffected persons. Van Driest reported this variant was not present in 400 reference alleles (200 from ethnically matched Caucasian Americans, and 200 from ethnically diverse African Americans; same as Bos et al 2014). (less)
Number of individuals with the variant: 26
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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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742965.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001921289.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001951130.1 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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MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis. | Zou X | Cell death & disease | 2022 | PMID: 36357371 |
The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes. | Sepp R | Diagnostics (Basel, Switzerland) | 2022 | PMID: 35626289 |
Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. | Kasak L | Human reproduction (Oxford, England) | 2022 | PMID: 35535697 |
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. | Burstein DS | Pediatric research | 2021 | PMID: 32746448 |
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: agibbs@bcm.edu | American journal of human genetics | 2019 | PMID: 31447099 |
Molecular characterization of Portuguese patients with dilated cardiomyopathy. | Sousa A | Revista portuguesa de cardiologia | 2019 | PMID: 30871747 |
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
Genetic background of Japanese patients with pediatric hypertrophic and restrictive cardiomyopathy. | Hayashi T | Journal of human genetics | 2018 | PMID: 29907873 |
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy. | van Waning JI | Journal of the American College of Cardiology | 2018 | PMID: 29447731 |
Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
Uncomplicated Pregnancy in a Patient Treated With Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. | Tomasov P | The Canadian journal of cardiology | 2017 | PMID: 28024942 |
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 |
Prevalence and Phenotypic Expression of Mutations in the MYH7, MYBPC3 and TNNT2 Genes in Families with Hypertrophic Cardiomyopathy in the South of Brazil: A Cross-Sectional Study. | Mattos BP | Arquivos brasileiros de cardiologia | 2016 | PMID: 27737317 |
Genotype-Dependent and -Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy. | Helms AS | Circulation | 2016 | PMID: 27688314 |
Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection. | Ingles J | Circulation. Cardiovascular genetics | 2015 | PMID: 26671970 |
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 |
Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. | Helms AS | Circulation. Cardiovascular genetics | 2014 | PMID: 25031304 |
Abnormal cardiac formation in hypertrophic cardiomyopathy: fractal analysis of trabeculae and preclinical gene expression. | Captur G | Circulation. Cardiovascular genetics | 2014 | PMID: 24704860 |
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. | Marsiglia JD | American heart journal | 2013 | PMID: 24093860 |
Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. | Lopes LR | Journal of medical genetics | 2013 | PMID: 23396983 |
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 |
Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy. | Curila K | Acta cardiologica | 2012 | PMID: 22455086 |
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. | Page SP | Circulation. Cardiovascular genetics | 2012 | PMID: 22267749 |
Left ventricular noncompaction: analysis of a pediatric population. | António M | Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology | 2011 | PMID: 21638988 |
Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice. | Fokstuen S | Journal of medical genetics | 2011 | PMID: 21239446 |
Clinical challenges of genotype positive (+)-phenotype negative (-) family members in hypertrophic cardiomyopathy. | Maron BJ | The American journal of cardiology | 2011 | PMID: 21185001 |
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. | Millat G | European journal of medical genetics | 2010 | PMID: 20624503 |
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 |
A child cohort study from southern Italy enlarges the genetic spectrum of hypertrophic cardiomyopathy. | Frisso G | Clinical genetics | 2009 | PMID: 19659763 |
[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. | García-Castro M | Revista espanola de cardiologia | 2009 | PMID: 19150014 |
Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. | Ehlermann P | BMC medical genetics | 2008 | PMID: 18957093 |
A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. | Fokstuen S | Human mutation | 2008 | PMID: 18409188 |
Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
Large-scale mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE. | Zeller R | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16715312 |
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15519027 |
Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. | Maron BJ | Journal of the American College of Cardiology | 2001 | PMID: 11499718 |
Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. | Niimura H | The New England journal of medicine | 1998 | PMID: 9562578 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYBPC3 | - | - | - | - |
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Text-mined citations for rs200411226 ...
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.