The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura 1998, Nanni 2003, Olivotto 2008, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42792) and has been identified in 4/124374 of European and in 2/23498 of African chromosomes by gnomAD (https://gnomad.broadinstitute.org/). The p.Glu258Lys variant is located in the last base of exon 6, which is part of the 5’ splice region. Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on case observations, segregation with disease, low frequency in the general population and observed impact on splicing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate.
NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
Pathogenic (33); Likely pathogenic (1)
Pathogenic (33); Likely pathogenic (1)
34 out of 38 submissions contributed to this classification
Help
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.
38
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys)
Variation ID: 42792 Accession: VCV000042792.102
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47348424 (GRCh38) [ NCBI UCSC ] 11: 47369975 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 4, 2015 Aug 4, 2026 Feb 2, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.772G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Glu258Lys missense NC_000011.10:g.47348424C>T NC_000011.9:g.47369975C>T NG_007667.1:g.9279G>A LRG_386:g.9279G>A LRG_386t1:c.772G>A LRG_386p1:p.Glu258Lys - Protein change
- E258K
- Other names
-
p.E258K:GAG>AAG
- Canonical SPDI
- NC_000011.10:47348423:C:T
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00003
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4724 | 4746 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2025 | RCV000035668.12 | |
| Pathogenic/Likely pathogenic (14) |
criteria provided, multiple submitters, no conflicts
|
Jan 22, 2026 | RCV000161125.30 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2025 | RCV000158310.53 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 2, 2026 | RCV000205517.28 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 13, 2025 | RCV000247227.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 21, 2022 | RCV000763244.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 12, 2024 | RCV001170208.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
Nov 2, 2021 | RCV002290957.2 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 07, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Primary familial hypertrophic cardiomyopathy |
Blueprint Genetics
Accession: SCV000188783.4
First in ClinVar: Sep 07, 2014 Last updated: Sep 22, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 14, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059319.6
First in ClinVar: May 03, 2013 Last updated: Jul 04, 2020 |
Comment:
show
The p.Glu258Lys variant in MYBPC3 has been reported in multiple HCM probands and segregated in many additional affected family members (Girolami 2006, Marston 2009, Niimura 1998, Nanni 2003, Olivotto 2008, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42792) and has been identified in 4/124374 of European and in 2/23498 of African chromosomes by gnomAD (https://gnomad.broadinstitute.org/). The p.Glu258Lys variant is located in the last base of exon 6, which is part of the 5’ splice region. Functional studies using patient RNA have shown that this alteration affects splicing, leading to skipping of exon 6, which is predicted to result in a frameshift, premature termination and therefore likely in a loss of function (Andersen 2004, Martson 2009). Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on case observations, segregation with disease, low frequency in the general population and observed impact on splicing. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 67
|
|
|
Pathogenic
(Feb 26, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367566.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
show
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,Ps4-MOD,PM2,PP1-M,PP3. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(Oct 28, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000208245.11
First in ClinVar: Feb 24, 2015 Last updated: Oct 09, 2016 |
Comment:
show
Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed as an Italian founder mutation (Girolami et al., 2006; Olivotto et al., 2008); Observed in 6/272910 global alleles in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of exon 6, which is part of the splice donor site; Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID 42792; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26671970, 30550750, 27532257, 23233322, 15114369, 29875424, 30165862, 28687478, 28679633, 30972196, 9562578, 19574547, 20359594, 18533079, 23283745, 22907696, 25031304, 23980194, 12951062, 26914223, 25971843, 21310275, 12707239, 15563892, 15519027, 23527136, 19590044, 15769446, 20031602, 22267749, 16858239, 28450932, 28790153, 29524613, 28916354, 12974739, 18957093, 27574918, 27267291, 27600940, 26869393, 25351510, 29447731, 30645170, 30446606, 31006259, 31737537, 31447099, 33673806, 33297573, 32686758) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 14, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Genetics and Molecular Pathology, SA Pathology
Accession: SCV004175449.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
show
The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 of the MYBPC3 gene which is predicted to change the amino acid glutamic acid at position 258 in the protein to lysine. The variant has been reported in excess of 70 probands with a clinical presentation of hypertrophic cardiomyopathy (PS4) and is reported to segregate with disease in multiple families (PMID#9562578, 16858239). Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044) (PS3). This variant has been reported in dbSNP (rs397516074), reported as disease causing in the HGMD database (CM981322) and is reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 42792). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(May 30, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001332760.4
First in ClinVar: May 31, 2020 Last updated: Feb 04, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 07, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002587108.3
First in ClinVar: Oct 29, 2022 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Focal-onset seizure (present) , Atypical behavior (present) , Status epilepticus (present) , Abnormal temper tantrums (present)
Sex: female
|
|
|
Likely pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe)
Accession: SCV000256170.1 First in ClinVar: Nov 04, 2015 Last updated: Nov 04, 2015 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Aug 01, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Phosphorus, Inc.
Accession: SCV000679779.1
First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 21, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744867.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 02, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypertrophic cardiomyopathy 4 |
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434957.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
show
The c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, 23233322, 25031304). This variant has an extremely low frequency in large databases of genetic variation in the general population. mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304). Therefore, this c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 03, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
3billion
Accession: SCV002058951.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
show
Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, PVS!_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000022, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Left ventricular hypertrophy (present)
Zygosity: 1 Single Heterozygote
Platform type: whole exome sequencing
Platform name: NovaSeq
|
|
|
Pathogenic
(Apr 06, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103243.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 05, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10 |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893880.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(May 02, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Illumina Laboratory Services, Illumina
Accession: SCV004014736.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
show
The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the available literature, this variant has been identified in a heterozygous state in greater than 50 unrelated individuals with hypertrophic cardiomyopathy (PMID: 18533079; PMID: 27532257). The highest frequency of this allele in the Genome Aggregation Database is 0.00004410 in the European (non-Finnish) population (version 3.1.2). This variant's nucleotide position coincides with a canonical splice donor site. Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194). A knock-in mouse carrying this variant has been developed and displays the hallmark phenotype of hypertrophic cardiomyopathy (PMID: 19590044). Based on the available evidence, the c.772G>A (p.Glu258Lys) variant is classified as pathogenic for hypertrophic cardiomyopathy. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Mar 21, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000996340.3
First in ClinVar: Nov 02, 2019 Last updated: Feb 08, 2025 |
Comment:
show
The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic". (less)
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Apr 03, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000231501.6
First in ClinVar: Jun 29, 2015 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 2
Zygosity: 2 Single Heterozygotes
Sex: mixed
|
|
|
Pathogenic
(May 09, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Center of Genomic medicine, Geneva, University Hospital of Geneva
Accession: SCV000693449.3
First in ClinVar: Mar 03, 2018 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Age: 30-39 years
Sex: female
|
|
|
Pathogenic
(Feb 26, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Loeys Lab, Universiteit Antwerpen
Accession: SCV001572568.2
First in ClinVar: Apr 30, 2021 Last updated: Apr 13, 2025 |
Comment:
show
This sequence change results in a missense variant in the MYBPC3 gene (p.(Glu258Lys)). This variant is present in population databases (GnomAD 6/272910). This variant has been reported in the literature in several unrelated individuals/families with HCM and cosegregated with disease (PP1) (PMID: 9562578; PMID: 12951062; PMID: 15519027; PMID: 12707239; PMID: 16858239). It was identified as a common variant among HCM patients in Italy (21% of the cases studied) (PMID: 18533079) (PS4). The variant affects a highly conserved position and alters the last base of exon 6, leading to skipping of exon 6. In cardiac tissue of HCM patients carrying the variant, no missense transcript was detected, indicating that the variant resulted in truncating mutant transcripts. These transcript however, did not result in any detectable truncated protein, since only wild-type protein was detected (PMID: 25031304). In neonatal rat cardiomyocytes it was shown that the truncated transcript underwent degradation by the ubiquitin-proteasome system ( PMID: 15769446) (PVS1). In murine a-engineered cardiac tissue the variant resulted in accelerated contractile kinetics, disruption of twitch force and absence of the interaction between cMyBP-C and myosin heavy chain sub-fragment 2 (PMID: 23980194) (PS3). In a knock-in mouse model homozygous mice showed left ventricular hypertrophy, reduced fractional shortening, and interstitial fibrosis; heterozygotes had no major phenotype.(PMID: 19590044). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.1828G>A, classified as variant of unknown significance). In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1; PS4;PS3). (less)
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Number of individuals with the variant: 1
Indication for testing: Cardiomyopathy, hypertrophic, 1
Test name: Haloplex CM-gene panel
Zygosity: 1 Single Heterozygote
Family history: no
Sex: female
Tissue: blood
Secondary finding: no
Platform type: next-gen sequencing
Platform name: MiSeq
|
|
|
Pathogenic
(Sep 11, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000747994.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Apr 12, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
Color Diagnostics, LLC DBA Color Health
Accession: SCV001359738.4
First in ClinVar: Jun 22, 2020 Last updated: May 03, 2025 |
Comment:
show
This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 in the MyBP-C motif of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 12974739, 14563344, 15563892, 16858239, 18533079, 19808356, 19574547, 23233322, 30645170, 34680864, 37498360, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
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Pathogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Primary familial hypertrophic cardiomyopathy |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917820.2
First in ClinVar: Jun 02, 2019 Last updated: May 03, 2025 |
Comment:
show
Variant summary: MYBPC3 c.772G>A (p.Glu258Lys) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. The variant allele was found at a frequency of 1.7e-05 in 241964 control chromosomes. The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). ClinVar contains an entry for this variant (Variation ID: 42792). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Aug 13, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV000320235.7
First in ClinVar: Oct 02, 2016 Last updated: Oct 05, 2025 |
Comment:
show
The c.772G>A (p.E258K) alteration is located in exon 6 (coding exon 6) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 772, causing the glutamic acid (E) at amino acid position 258 to be replaced by a lysine (K). However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (6/272910) total alleles studied. The highest observed frequency was 0.009% (2/23498) of African alleles. This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) with co-segregation and a suggested founder effect (Niimura, 1998; Girolami, 2006; Bongini, 2016). In one study, RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). Based on the available evidence, this alteration is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 20, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV005398702.2
First in ClinVar: Nov 24, 2024 Last updated: Dec 01, 2025 |
Comment:
show
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant is reported in the literature as p.(Glu258Lys). However, functional studies showed exon 6 skipping resulting in p.(Val219Argfs*42), predicted to undergo nonsense-mediated decay (NMD) (PMIDs: 15114369, 25031304); Variant is present in gnomAD <0.01 (v4: 54 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar, and has been reported in the literature in heterozygous individuals with hypertrophic cardiomyopathy (VCGS internal data; PMIDs: 25031304, 27532257); Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM); Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044); Inheritance information for this variant is not currently available in this individual. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Feb 02, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260690.14
First in ClinVar: Jan 31, 2016 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein (p.Glu258Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs397516074, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This variant is also known as E264K. ClinVar contains an entry for this variant (Variation ID: 42792). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
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Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV007495856.1
First in ClinVar: Mar 01, 2026 Last updated: Mar 01, 2026 |
Comment:
show
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(Jan 22, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007593644.1
First in ClinVar: May 16, 2026 Last updated: May 16, 2026 |
Comment:
show
This is a nonsynonymous variant in the MYBPC3 gene (OMIM: 600958). Pathogenic variants in this gene have been associated with autosomal dominant hypertrophic cardiomyopathy 4. Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.616) but functional studies have shown that this variant results in abnormal splicing, leading to skipping of exon 6, which is expected to cause loss of function (PMID: 25031304, 30645170) (PVS1). This variant has been reported in many unrelated affected individuals (PMID: 27532257, 12707239, 12707239, 22267749, 23233322) (PS4) and it has been observed to segregate with disease in at least 5 individuals from one family (PMID: 9562578) (PP1). This variant has a 0.0042% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy 4. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
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Pathogenic
(Jan 31, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Dasa
Accession: SCV007599081.1
First in ClinVar: May 30, 2026 Last updated: May 30, 2026 |
Comment:
show
NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys) is a missense variant that results in the substitution of glutamic acid with lysine. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 15769446; PMID: 19590044; PMID: 25031304; PMID: 20359594; PMID: 9562578). This variant has been recurrently observed in individuals with related phenotype (PMID: 15769446; PMID: 19590044; PMID: 25031304; PMID: 20359594; PMID: 9562578). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001961282.33
First in ClinVar: Oct 08, 2021 Last updated: Jul 27, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Oct 28, 2015)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924856.2
First in ClinVar: Jun 29, 2019 Last updated: Aug 04, 2026 |
Observation: 1
Collection method: provider interpretation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: provider interpretation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 29, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199347.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004834726.2
First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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)
|
Comment:
show
This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 in the MyBP-C motif of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 12974739, 14563344, 15563892, 16858239, 18533079, 19808356, 19574547, 23233322, 30645170, 34680864, 37498360, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 6
Zygosity: 6 Single Heterozygotes
|
|
|
Pathogenic
(Sep 21, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. |
New York Genome Center
Accession: SCV003925302.2
First in ClinVar: May 20, 2023 Last updated: Dec 22, 2024 |
Comment:
show
The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found to segregate in many additional affected family members [PMID:9562578]. This variant has been deposited in ClinVar [ClinVar ID: 42792] as Pathogenic/Likely Pathogenic. The c.772G>A variant is observed in 17 alleles (0.0021% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.772G>A variant in MYBPC3 is located in exon 6 of this 35-exon gene and is predicted to replace a moderately conserved glutamic acid with lysine amino acid at position 285 p.(Arg123Gln) in the phosphorylation domain of the c1 motif of the encoded protein [PMID:28658286,23233322, 15114369]. In addition, the c.772G>A variant is located one nucleotide away from the exon-intron junction of exon 6, therefore it may also affect the splicing. In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]. In silico predictions are inconclusive for p.(Arg123Gln) variant's effect [(CADD v1.6 = 51, REVEL = 0.616)]. Based on available evidence, this c.772G>A p.(Glu258Lys) variant identified in MYBPC3 is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Cardiomyopathy (present)
Test name: whole genome sequencing
Zygosity: 1 Single Heterozygote
Secondary finding: no
Platform name: NovaSeq 6000
|
|
|
Pathogenic
(Feb 16, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Accession: SCV006109860.1
First in ClinVar: Jul 05, 2025 Last updated: Jul 05, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hypertrophic cardiomyopathy 4 |
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733061.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 02, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Left ventricular noncompaction 10 |
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002583319.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
hypertrophic cardiomyopathy |
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics
Accession: SCV005374520.1
First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024 |
Observation: 1
Collection method: research
Allele origin: unknown
Affected status: yes
Observation 1
Collection method: research
Allele origin: unknown
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001954161.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,Ps4-MOD,PM2,PP1-M,PP3.
Comment:
Reported to segregate with disease in multiple families (Niimura et al., 1998; Richard et al., 2003; Ho et al., 2009; Zhao et al., 2017); Proposed as an Italian founder mutation (Girolami et al., 2006; Olivotto et al., 2008); Observed in 6/272910 global alleles in large population cohorts (Lek et al., 2016); Located in the last nucleotide position of exon 6, which is part of the splice donor site; Functional studies have demonstrated that the E258K variant leads to aberrant gene splicing of exon 6 (Andersen et al., 2004; Vignier et al., 2009; Helms et al., 2014); Additional studies suggest this variant may result in rapid protein degradation (Sarikas et al., 2005; Vignier et al., 2009) or, if abnormal protein is expressed, it may lead to altered protein interaction and contractile kinetics (De Lange et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID 42792; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26671970, 30550750, 27532257, 23233322, 15114369, 29875424, 30165862, 28687478, 28679633, 30972196, 9562578, 19574547, 20359594, 18533079, 23283745, 22907696, 25031304, 23980194, 12951062, 26914223, 25971843, 21310275, 12707239, 15563892, 15519027, 23527136, 19590044, 15769446, 20031602, 22267749, 16858239, 28450932, 28790153, 29524613, 28916354, 12974739, 18957093, 27574918, 27267291, 27600940, 26869393, 25351510, 29447731, 30645170, 30446606, 31006259, 31737537, 31447099, 33673806, 33297573, 32686758)
Comment:
The MYBPC3 c.772G>A variant is classified as Pathogenic (PS3, PS4) MYBPC3 c.772G>A is a single nucleotide variant located at the last nucleotide of exon 6/35 of the MYBPC3 gene which is predicted to change the amino acid glutamic acid at position 258 in the protein to lysine. The variant has been reported in excess of 70 probands with a clinical presentation of hypertrophic cardiomyopathy (PS4) and is reported to segregate with disease in multiple families (PMID#9562578, 16858239). Well-established functional studies show this variant impacts splicing, resulting in a deletion of exon 6 and downstream truncation of the MYBPC3 protein (PMID#3980194, 25031304, 28679633, 30645170, 34097875, 19590044) (PS3). This variant has been reported in dbSNP (rs397516074), reported as disease causing in the HGMD database (CM981322) and is reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 42792).
Comment:
Criteria applied: PS3,PS4,PM5
Comment:
The c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathies (PMID: 9562578, 12707239, 15114369, 15563892, 16858239, 18533079, 23233322, 25031304). This variant has an extremely low frequency in large databases of genetic variation in the general population. mRNA studies demonstrated that this variant resulted in skipping of exon 6 (PMID: 15114369, 25031304). Therefore, this c.772G>A (p.Glu258Lys) variant in the MYBPC3 gene is classified as pathogenic.
Comment:
Missense variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 25031304, PVS!_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000022, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042792). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PS3, PS4, PP1, PP3
Comment:
The MYBPC3 c.772G>A (p.Glu258Lys) missense variant results in the substitution of glutamic acid at amino acid position 258 with lysine. Across a selection of the available literature, this variant has been identified in a heterozygous state in greater than 50 unrelated individuals with hypertrophic cardiomyopathy (PMID: 18533079; PMID: 27532257). The highest frequency of this allele in the Genome Aggregation Database is 0.00004410 in the European (non-Finnish) population (version 3.1.2). This variant's nucleotide position coincides with a canonical splice donor site. Functional experiments using patient tissues have demonstrated an effect on splicing that leads to skipping of exon 6, which results in nonsense-mediated mRNA decay due to a premature stop codon (PMID: 15114369; PMID: 19574547). In addition, transgenic rescue experiments performed in cultured murine cardiomyocytes have demonstrated reduced contractile force and altered contractile kinetics due to the presence of the p.Glu258Lys variant independent of any effects on splicing (PMID: 23980194). A knock-in mouse carrying this variant has been developed and displays the hallmark phenotype of hypertrophic cardiomyopathy (PMID: 19590044). Based on the available evidence, the c.772G>A (p.Glu258Lys) variant is classified as pathogenic for hypertrophic cardiomyopathy.
Comment:
The MYBPC3 Glu258Lys is a rare variant, with an allele frequency of 0.000039 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). This variant has been reported in multiple unrelated HCM patients (see references), and is observed to be shared in up to ~14% of unrelated HCM cases in Italian cohorts, suggesting a founder effect (Girolami et al, 2006; Olivotto et al, 2008). Segregation analyses support its pathogenic role (Niimura et al., 1998; Girolami et al., 2006). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict this variant to be disease causing. Furthermore, this variant affects the splice site consensus sequence (last base of exon 6) and has been shown to result in truncated MYBPC3 protein due to exon skipping (Anderson et al., 2004; Sarikas et al., 2005; Helms AS, et al., 2014). Functional studies have shown that the truncated protein is incorporated into cardiac sarcomeres and impairs contractile function (De Lange et al., 2013). We have identified MYBPC3 Glu258Lys in 3 HCM probands. In summary, based on rarity in the general population, observation in multiple unrelated HCM cases and because loss of function is a mechanism of disease for MYBPC3, we classify this variant as "pathogenic".
Comment:
This sequence change results in a missense variant in the MYBPC3 gene (p.(Glu258Lys)). This variant is present in population databases (GnomAD 6/272910). This variant has been reported in the literature in several unrelated individuals/families with HCM and cosegregated with disease (PP1) (PMID: 9562578; PMID: 12951062; PMID: 15519027; PMID: 12707239; PMID: 16858239). It was identified as a common variant among HCM patients in Italy (21% of the cases studied) (PMID: 18533079) (PS4). The variant affects a highly conserved position and alters the last base of exon 6, leading to skipping of exon 6. In cardiac tissue of HCM patients carrying the variant, no missense transcript was detected, indicating that the variant resulted in truncating mutant transcripts. These transcript however, did not result in any detectable truncated protein, since only wild-type protein was detected (PMID: 25031304). In neonatal rat cardiomyocytes it was shown that the truncated transcript underwent degradation by the ubiquitin-proteasome system ( PMID: 15769446) (PVS1). In murine a-engineered cardiac tissue the variant resulted in accelerated contractile kinetics, disruption of twitch force and absence of the interaction between cMyBP-C and myosin heavy chain sub-fragment 2 (PMID: 23980194) (PS3). In a knock-in mouse model homozygous mice showed left ventricular hypertrophy, reduced fractional shortening, and interstitial fibrosis; heterozygotes had no major phenotype.(PMID: 19590044). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.1828G>A, classified as variant of unknown significance). In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1; PS4;PS3).
Comment:
PVS1, PS3, PS4, PP1_strong, PM2
Comment:
This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 in the MyBP-C motif of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 12974739, 14563344, 15563892, 16858239, 18533079, 19808356, 19574547, 23233322, 30645170, 34680864, 37498360, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Variant summary: MYBPC3 c.772G>A (p.Glu258Lys) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. 5/5 programs via Alamut predict that this variant affects normal splicing. Multiple functional studies confirmed that the variant leads to exon 6 skipping resulting in a premature stop codon (Anderson_2004, Helms_2014). Heterozygous loss-of-function due to mutations in the MYBPC3 gene is an established disease mechanism in HCM. The variant allele was found at a frequency of 1.7e-05 in 241964 control chromosomes. The variant has been recurrently found in numerous patients with HCM and is reported to cosegregate with the disease (Niimura_1998; Girolami_2006). ClinVar contains an entry for this variant (Variation ID: 42792). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.772G>A (p.E258K) alteration is located in exon 6 (coding exon 6) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 772, causing the glutamic acid (E) at amino acid position 258 to be replaced by a lysine (K). However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (6/272910) total alleles studied. The highest observed frequency was 0.009% (2/23498) of African alleles. This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) with co-segregation and a suggested founder effect (Niimura, 1998; Girolami, 2006; Bongini, 2016). In one study, RT-qPCR analysis showed that the altered allele resulted in skipping of exon 6 and all of the mutant transcripts were truncated (Helms AS et al. Circ Cardiovasc Genet. 2014;7(4):434-43). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant is reported in the literature as p.(Glu258Lys). However, functional studies showed exon 6 skipping resulting in p.(Val219Argfs*42), predicted to undergo nonsense-mediated decay (NMD) (PMIDs: 15114369, 25031304); Variant is present in gnomAD <0.01 (v4: 54 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar, and has been reported in the literature in heterozygous individuals with hypertrophic cardiomyopathy (VCGS internal data; PMIDs: 25031304, 27532257); Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM); Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197); Variants in this gene are known to have variable expressivity (PMID: 32841044); Inheritance information for this variant is not currently available in this individual.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the MYBPC3 protein (p.Glu258Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs397516074, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 12707239, 15563892, 18533079, 20031602, 22267749, 23233322). This variant is also known as E264K. ClinVar contains an entry for this variant (Variation ID: 42792). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 15769446, 19590044, 23980194). Studies have shown that this missense change results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15114369, 19574547, 25031304). For these reasons, this variant has been classified as Pathogenic.
Comment:
Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Comment:
This is a nonsynonymous variant in the MYBPC3 gene (OMIM: 600958). Pathogenic variants in this gene have been associated with autosomal dominant hypertrophic cardiomyopathy 4. Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.616) but functional studies have shown that this variant results in abnormal splicing, leading to skipping of exon 6, which is expected to cause loss of function (PMID: 25031304, 30645170) (PVS1). This variant has been reported in many unrelated affected individuals (PMID: 27532257, 12707239, 12707239, 22267749, 23233322) (PS4) and it has been observed to segregate with disease in at least 5 individuals from one family (PMID: 9562578) (PP1). This variant has a 0.0042% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy 4.
Comment:
NM_000256.3(MYBPC3):c.772G>A (p.Glu258Lys) is a missense variant that results in the substitution of glutamic acid with lysine. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 15769446; PMID: 19590044; PMID: 25031304; PMID: 20359594; PMID: 9562578). This variant has been recurrently observed in individuals with related phenotype (PMID: 15769446; PMID: 19590044; PMID: 25031304; PMID: 20359594; PMID: 9562578). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic.
Comment:
MYBPC3: PP1:Strong, PM2, PS4:Moderate, PVS1:Moderate, PM5:Supporting
Comment:
This variant alters the conserved c.G nucleotide at the last nucleotide position of exon 6 in the MyBP-C motif of the MYBPC3 gene. RNA studies using blood and myocardial samples from carriers have shown that this variant causes out-of-frame skipping of exon 6, resulting in premature truncation (PMID: 15114369, 19574547, 25031304, 30645170). A study using engineered mouse cardiac tissue has shown that this variant disrupts the interaction between MYBPC3 and myosin protein and accelerates contractile kinetics (PMID: 23980194). In a knock-in mouse model, this variant causes left ventricular hypertrophy and reduced fractional shortening, consistent with hypertrophic cardiomyopathy phenotype (PMID: 19590044). This variant has been reported in over 50 individuals affected with hypertrophic cardiomyopathy from various populations (PMID: 12707239, 12951062, 12974739, 14563344, 15563892, 16858239, 18533079, 19808356, 19574547, 23233322, 30645170, 34680864, 37498360, Marschall et al., 2019) and is particularly common in the Italian population (PMID: 16858239, 18533079). This variant has been shown to segregate with disease in a family study (PMID: 9562578). This variant has been identified in 6/272910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.772G>A variant in MYBPC3 has previously been reported in individuals with noncompaction cardiomyopathy [PMID:29447731], hypertrophic cardiomyopathy [PMID:15114369,25031304, 22267749, 23233322, 30645170, 30972196], and was found to segregate in many additional affected family members [PMID:9562578]. This variant has been deposited in ClinVar [ClinVar ID: 42792] as Pathogenic/Likely Pathogenic. The c.772G>A variant is observed in 17 alleles (0.0021% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.772G>A variant in MYBPC3 is located in exon 6 of this 35-exon gene and is predicted to replace a moderately conserved glutamic acid with lysine amino acid at position 285 p.(Arg123Gln) in the phosphorylation domain of the c1 motif of the encoded protein [PMID:28658286,23233322, 15114369]. In addition, the c.772G>A variant is located one nucleotide away from the exon-intron junction of exon 6, therefore it may also affect the splicing. In vitro functional RNA studies using blood and myocardial samples have shown to cause out-of-frame skipping of exon 6, resulting in premature truncation cells carrying c.772G>A variant [PMID: 15114369, 25031304, 30645170]. Besides, this variant has demonstrated to alter protein interactions, contractile kinetics and caused left ventricular hypertrophy, reduced fractional shortening consistent with hypertrophic cardiomyopathy phenotype in mouse models [PMID: 19590044]. In silico predictions are inconclusive for p.(Arg123Gln) variant's effect [(CADD v1.6 = 51, REVEL = 0.616)]. Based on available evidence, this c.772G>A p.(Glu258Lys) variant identified in MYBPC3 is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of variants in genes associated with hypertrophic cardiomyopathy in Mexican patients. | García-Vielma C | Molecular genetics and genomics : MGG | 2023 | PMID: 37498360 |
| Myocardial Deformation Analysis in MYBPC3 and MYH7 Related Sarcomeric Hypertrophic Cardiomyopathy-The Graz Hypertrophic Cardiomyopathy Registry. | Höller V | Genes | 2021 | PMID: 34680864 |
| Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy. | Suay-Corredera C | The Journal of biological chemistry | 2021 | PMID: 34097875 |
| Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. | Helms AS | Circulation. Genomic and precision medicine | 2020 | PMID: 32841044 |
| Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy. | Singer ES | Circulation. Genomic and precision medicine | 2019 | PMID: 30645170 |
| Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing. | Ito K | Proceedings of the National Academy of Sciences of the United States of America | 2017 | PMID: 28679633 |
| 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 |
| Impact of Genotype on the Occurrence of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy. | Bongini C | The American journal of cardiology | 2016 | PMID: 26869393 |
| An Investigation of the Molecular Mechanism of Double cMyBP-C Mutation in a Patient with End-Stage Hypertrophic Cardiomyopathy. | Gajendrarao P | Journal of cardiovascular translational research | 2015 | PMID: 25971843 |
| Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
| Sarcomere mutation-specific expression patterns in human hypertrophic cardiomyopathy. | Helms AS | Circulation. Cardiovascular genetics | 2014 | PMID: 25031304 |
| Rare variants in genes encoding MuRF1 and MuRF2 are modifiers of hypertrophic cardiomyopathy. | Su M | International journal of molecular sciences | 2014 | PMID: 24865491 |
| Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
| Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
| A systematic approach to assessing the clinical significance of genetic variants. | Duzkale H | Clinical genetics | 2013 | PMID: 24033266 |
| E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction. | De Lange WJ | The Journal of general physiology | 2013 | PMID: 23980194 |
| Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy. | Núñez L | Circulation journal : official journal of the Japanese Circulation Society | 2013 | PMID: 23782526 |
| Comparison of echocardiographic and cardiac magnetic resonance imaging in hypertrophic cardiomyopathy sarcomere mutation carriers without left ventricular hypertrophy. | Valente AM | Circulation. Cardiovascular genetics | 2013 | PMID: 23690394 |
| Molecular modeling of disease causing mutations in domain C1 of cMyBP-C. | Gajendrarao P | PloS one | 2013 | PMID: 23527136 |
| Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
| Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program. | Kassem HSh | Journal of cardiovascular translational research | 2013 | PMID: 23233322 |
| Uptake of cardiac screening and genetic testing among hypertrophic and dilated cardiomyopathy families. | Miller EM | Journal of genetic counseling | 2013 | PMID: 23054336 |
| A case of compound mutations in the MYBPC3 gene associated with biventricular hypertrophy and neonatal death. | Marziliano N | Neonatology | 2012 | PMID: 22907696 |
| Prevalence and clinical profile of myocardial crypts in hypertrophic cardiomyopathy. | Maron MS | Circulation. Cardiovascular imaging | 2012 | PMID: 22563033 |
| 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 |
| Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. | Olivotto I | Journal of the American College of Cardiology | 2011 | PMID: 21835320 |
| [Study of mutations causing hypertrophic cardiomyopathy in a group of patients from Espirito Santo, Brazil]. | Marsiglia JD | Arquivos brasileiros de cardiologia | 2010 | PMID: 20414521 |
| Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations. | Girolami F | Journal of the American College of Cardiology | 2010 | PMID: 20359594 |
| Efficacy of catheter ablation for atrial fibrillation in hypertrophic cardiomyopathy: impact of age, atrial remodelling, and disease progression. | Di Donna P | Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | 2010 | PMID: 20173211 |
| Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. | Predmore JM | Circulation | 2010 | PMID: 20159828 |
| Echocardiographic strain imaging to assess early and late consequences of sarcomere mutations in hypertrophic cardiomyopathy. | Ho CY | Circulation. Cardiovascular genetics | 2009 | PMID: 20031602 |
| Expression patterns of cardiac myofilament proteins: genomic and protein analysis of surgical myectomy tissue from patients with obstructive hypertrophic cardiomyopathy. | Theis JL | Circulation. Heart failure | 2009 | PMID: 19808356 |
| Nonsense-mediated mRNA decay and ubiquitin-proteasome system regulate cardiac myosin-binding protein C mutant levels in cardiomyopathic mice. | Vignier N | Circulation research | 2009 | PMID: 19590044 |
| Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
| Adverse events in families with hypertrophic or dilated cardiomyopathy and mutations in the MYBPC3 gene. | Ehlermann P | BMC medical genetics | 2008 | PMID: 18957093 |
| Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. | Olivotto I | Mayo Clinic proceedings | 2008 | PMID: 18533079 |
| ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. | Richards CS | Genetics in medicine : official journal of the American College of Medical Genetics | 2008 | PMID: 18414213 |
| Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
| Crystal structure of the C1 domain of cardiac myosin binding protein-C: implications for hypertrophic cardiomyopathy. | Govada L | Journal of molecular biology | 2008 | PMID: 18374358 |
| Contribution of inherited heart disease to sudden cardiac death in childhood. | Hofman N | Pediatrics | 2007 | PMID: 17908752 |
| A molecular screening strategy based on beta-myosin heavy chain, cardiac myosin binding protein C and troponin T genes in Italian patients with hypertrophic cardiomyopathy. | Girolami F | Journal of cardiovascular medicine (Hagerstown, Md.) | 2006 | PMID: 16858239 |
| Impairment of the ubiquitin-proteasome system by truncated cardiac myosin binding protein C mutants. | Sarikas A | Cardiovascular research | 2005 | PMID: 15769446 |
| Mutations profile in Chinese patients with hypertrophic cardiomyopathy. | Song L | Clinica chimica acta; international journal of clinical chemistry | 2005 | PMID: 15563892 |
| Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15519027 |
| Genetic and phenotypic characterization of mutations in myosin-binding protein C (MYBPC3) in 81 families with familial hypertrophic cardiomyopathy: total or partial haploinsufficiency. | Andersen PS | European journal of human genetics : EJHG | 2004 | PMID: 15114369 |
| The 2373insG mutation in the MYBPC3 gene is a founder mutation, which accounts for nearly one-fourth of the HCM cases in the Netherlands. | Alders M | European heart journal | 2003 | PMID: 14563344 |
| Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. | Erdmann J | Clinical genetics | 2003 | PMID: 12974739 |
| Hypertrophic cardiomyopathy: two homozygous cases with "typical" hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. | Nanni L | Biochemical and biophysical research communications | 2003 | PMID: 12951062 |
| Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. | Richard P | Circulation | 2003 | PMID: 12707239 |
| 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 |
| Botulism intoxication after surgery in the gut. | Isacsohn M | Israel journal of medical sciences | 1985 | PMID: 3980194 |
| - | - | - | - | PMID: 397516074 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYBPC3 | - | - | - | - |
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Text-mined citations for rs397516074 ...
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Record last updated Aug 04, 2026
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.