This variant affects the last nucleotide of exon 18 of MYBPC3 gene and may therefore alter native splicing. This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy (PMID: 22455086, 25849606, 25086479, 27532257, 31006259). In-vitro studies in mammalian cells using a mini gene assays have shown that this missense change results in aberrant splicing (PMID: 25849606, 28679633). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (5/166884) and thus is presumed to be rare. The c.1790G>A (p.Arg597Gln) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1790G>A (p.Arg597Gln) variant is classified as Likely Pathogenic.
NM_000256.3(MYBPC3):c.1790G>A (p.Arg597Gln)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
Pathogenic (9); Likely pathogenic (6)
Pathogenic (9); Likely pathogenic (6)
15 out of 18 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.
18
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000256.3(MYBPC3):c.1790G>A (p.Arg597Gln)
Variation ID: 164098 Accession: VCV000164098.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47341991 (GRCh38) [ NCBI UCSC ] 11: 47363542 (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 May 29, 2016 May 30, 2026 Jan 24, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.1790G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Arg597Gln missense NC_000011.10:g.47341991C>T NC_000011.9:g.47363542C>T NG_007667.1:g.15712G>A LRG_386:g.15712G>A LRG_386t1:c.1790G>A LRG_386p1:p.Arg597Gln - Protein change
- R597Q
- Other names
- -
- Canonical SPDI
- NC_000011.10:47341990: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.
-
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
- 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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 23, 2024 | RCV000248201.8 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2026 | RCV000497973.21 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Oct 28, 2024 | RCV000505707.10 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 9, 2024 | RCV001170951.5 | |
|
MYBPC3-related cardiomyopathies
|
Likely pathogenic (1) |
criteria provided, single submitter
|
May 23, 2020 | RCV001731397.2 |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 30, 2025 | RCV003989331.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV005644524.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 23, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
MYBPC3-related cardiomyopathies
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984857.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
show
This variant affects the last nucleotide of exon 18 of MYBPC3 gene and may therefore alter native splicing. This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy (PMID: 22455086, 25849606, 25086479, 27532257, 31006259). In-vitro studies in mammalian cells using a mini gene assays have shown that this missense change results in aberrant splicing (PMID: 25849606, 28679633). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (5/166884) and thus is presumed to be rare. The c.1790G>A (p.Arg597Gln) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1790G>A (p.Arg597Gln) variant is classified as Likely 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
|
|
|
Likely pathogenic
(Oct 19, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333605.2
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
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 29, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Accession: SCV004807667.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 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
(Oct 28, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000208050.8
First in ClinVar: Feb 24, 2015 Last updated: Nov 17, 2024 |
Comment:
show
Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 22455086, 23674513, 23508784, 25086479, 24111713, 27600940, 31513939, 31110529, 29255176, 32369506, 34400558, 36291626, 35653365, 36264615, 37652022, 37342443); Published functional studies demonstrate a damaging effect as this variant results in abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); Not observed at significant frequency in large population cohorts (gnomAD); Located in the last nucleotide position of the exon, which is part of the splice donor site; This variant is associated with the following publications: (PMID: 27532257, 28679633, 31513939, 26553696, 22455086, 31006259, 32824488, 32841044, 31323898, 27600940, 23674513, 23508784, 24111713, 29255176, 34400558, 36291626, 36335097, 34503678, 32369506, 35653365, 31110529, 25086479, 25849606, 35130036, 36264615, 37652022, 36136372, 37342443, 34461741) (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
(Sep 02, 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: SCV004828387.2
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
The c.1790G>A (p.Arg597Gln) variant of the MYBPC3 gene is predicted to replace arginine with glutamine at codon 597 of the MYBPC3 protein. This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. Studies using in vitro hybrid minigene assays suggested aberrant splicing impact from the c.1790G>A variant and an altered mRNA splicing leading to a premature termination codon (PMID: 28679633). This variant has been observed in multiple individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23674513, 24111713, 25086479, 27532257, 27600940, 22455086, 25849606). It has also been observed to segregate with disease in 1 affected relative (PMID: 25086479). This variant has been identified in 5/166884 chromosomes in the general population according to the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on these evidence, c.1790G>A (p.Arg597Gln) variant in MYBPC3 gene is interpreted 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: 3
Zygosity: 3 Single Heterozygotes
|
|
|
Likely pathogenic
(Sep 23, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV000318810.8
First in ClinVar: Oct 02, 2016 Last updated: Jan 13, 2025 |
Comment:
show
The c.1790G>A variant (also known as p.R597Q), located in coding exon 18 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1790. The amino acid change results in arginine to glutamine at codon 597, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 18, which makes it likely to have some effect on normal mRNA splicing. This variant also has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Curila K et al. Acta Cardiol. 2012;67:23-9; Berge KE et al. Clin Genet. 2014;86:355-60; Witjas-Paalberends ER et al. Cardiovasc. Res. 2013 Aug;99(3):432-41; Chiou KR et al. J Cardiol. 2015;65:250-6; Walsh R et al. Genet Med. 2017;19:192-203). In one study, an in vitro minigene splicing assay has suggested this variant results in out-of-frame skipping of exon 18 which results in the introduction of a premature truncation codon (Millat G et al. DNA Cell Biol. 2015;34:489-96), and a second minigene assay has also suggested aberrant splicing impact (Ito K. Proc. Natl. Acad. Sci. U.S.A.. 2017 Jul;114(29):7689-7694). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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
(Sep 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
Color Diagnostics, LLC DBA Color Health
Accession: SCV006061203.1
First in ClinVar: May 03, 2025 Last updated: May 03, 2025 |
Comment:
show
This variant changes the last nucleotide c.G of exon 18 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 18 splice donor site. Functional mini-gene assays have shown that this variant is expected to cause an out-of-frame skipping of exon 18 (PMID: 25849606, 28679633). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 22455086, 23674513, 24111713, 25086479, 25849606, 27532257, 27600940, 27885498, 29255176, 31110529, 31323898, 33495596, 33495597, 33732734, 36291626, 38757491, 25086479, 29255176, 37342443). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 25086479, 29255176, 37342443). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 37342443). This variant has been identified in 5/166884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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
|
|
|
Pathogenic
(Dec 30, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007593607.1
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 semidominant hypertrophic cardiomyopathy 4. Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.387), but functional studies have shown that this variant alters splicing and results in the skipping of exon 18 and loss of function, which is a known disease mechanism for MYBPC3 in this disorder (PMID: 28679633, 25849606) (PVS1). This variant has been reported in several affected individuals (PMID: 37652022, 27532257, 22455086, 22455086, 27532257, 31006259, 34400558) (PS4) and it has been observed to segregate with disease in at least two individuals from one family (PMID: 25086479). This variant has a 0.0176% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). . Based on the evidence, this variant is classified as pathogenic for autosomal dominant or autosomal recessive hypertrophic cardiomyopathy 4. (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
|
|
|
Likely pathogenic
(Feb 25, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV007597172.1
First in ClinVar: May 30, 2026 Last updated: May 30, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Secondary finding: yes
|
|
|
Likely pathogenic
(Sep 01, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198884.5
First in ClinVar: Feb 02, 2015 Last updated: May 29, 2021 |
Comment:
show
The p.Arg597Gln variant in MYBPC3 has been identified in at least 15 individuals with hypertrophic cardiomyopathy and segregated with disease in 1 affected relative (Berge 2014, Curila 2012, Chiou 2015, Millat 2015, Walsh 2016, LMM data, GeneDx pers. comm., Ambry pers comm., Invitae pers. comm., Stanford pers. comm., CHEO pers. comm, SHaRe database). The variant has been identified in 5/166884 chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant is located in the last three bases of the exon, which is part of the 5' splice region. An in vitro functional study showed that cells harboring this variant produced a shorter mRNA product than wild type cells, consistent with skipping of exon 18 (Millat 2015). Computational tools also suggest some impact to splicing. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PS3_Supporting, PP3. (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: 4
|
|
|
Pathogenic
(Feb 09, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
|
Center for Human Genetics, University of Leuven
Accession: SCV000579519.2
First in ClinVar: Aug 20, 2017 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
Number of individuals with the variant: 2
Test name: Cardiocapture - Leuven
Family history: yes
Age: 21-27 years
Sex: male
Ethnicity/Population group: Asian
Geographic origin: Iraq
Secondary finding: no
Platform type: NGS
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Left ventricular noncompaction 10
(Autosomal dominant inheritance)
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV006333733.1
First in ClinVar: Sep 27, 2025 Last updated: Sep 27, 2025 |
Comment:
show
The observed missense variant, splice region c.1790G>A(p.Arg597Gln) in MYBPC3 gene has been reported previously in multiple individuals with cardiomyopathy (Cecconi M, et al., 2016, Walsh R, et al., 2017). Experimental studies have shown that this variant affects the function of the gene (Millat G, et al., 2015). For these reasons, this variant has been 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
|
|
|
Likely pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Juno Genomics, Hangzhou Juno Genomics, Inc
Accession: SCV005417288.2
First in ClinVar: Nov 30, 2024 Last updated: Oct 05, 2025 |
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.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. (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
(Jul 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV007096757.2
First in ClinVar: Nov 08, 2025 Last updated: Dec 01, 2025 |
Comment:
show
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 24 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from Arg to Gln. This variant impacts the last nucleotide of exon 18 and as a result may affect splicing. A minigene assay has shown abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); 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); Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 53 heterozygote(s), 0 homozygote(s)); Variant is located in the annotated immunoglobulin I-set domain (DECIPHER); Missense variant with inconclusive in silico prediction and/or uninformative conservation; 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); This variant has been shown to be maternally inherited by trio analysis. (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 24, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000749869.9
First in ClinVar: Aug 20, 2017 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 597 of the MYBPC3 protein (p.Arg597Gln). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs727503195, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23674513, 24111713, 25086479, 27532257, 27600940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164098). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25849606, 28679633). 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
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001972448.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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
|
|
|
Likely 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: SCV001957502.1 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
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
hypertrophic cardiomyopathy |
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics
Accession: SCV005374557.1
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
|
|
Comment:
Comment:
Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 22455086, 23674513, 23508784, 25086479, 24111713, 27600940, 31513939, 31110529, 29255176, 32369506, 34400558, 36291626, 35653365, 36264615, 37652022, 37342443); Published functional studies demonstrate a damaging effect as this variant results in abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); Not observed at significant frequency in large population cohorts (gnomAD); Located in the last nucleotide position of the exon, which is part of the splice donor site; This variant is associated with the following publications: (PMID: 27532257, 28679633, 31513939, 26553696, 22455086, 31006259, 32824488, 32841044, 31323898, 27600940, 23674513, 23508784, 24111713, 29255176, 34400558, 36291626, 36335097, 34503678, 32369506, 35653365, 31110529, 25086479, 25849606, 35130036, 36264615, 37652022, 36136372, 37342443, 34461741)
Comment:
The c.1790G>A (p.Arg597Gln) variant of the MYBPC3 gene is predicted to replace arginine with glutamine at codon 597 of the MYBPC3 protein. This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. Studies using in vitro hybrid minigene assays suggested aberrant splicing impact from the c.1790G>A variant and an altered mRNA splicing leading to a premature termination codon (PMID: 28679633). This variant has been observed in multiple individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23674513, 24111713, 25086479, 27532257, 27600940, 22455086, 25849606). It has also been observed to segregate with disease in 1 affected relative (PMID: 25086479). This variant has been identified in 5/166884 chromosomes in the general population according to the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on these evidence, c.1790G>A (p.Arg597Gln) variant in MYBPC3 gene is interpreted as pathogenic.
Comment:
The c.1790G>A variant (also known as p.R597Q), located in coding exon 18 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1790. The amino acid change results in arginine to glutamine at codon 597, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 18, which makes it likely to have some effect on normal mRNA splicing. This variant also has been reported in hypertrophic cardiomyopathy (HCM) cohorts (Curila K et al. Acta Cardiol. 2012;67:23-9; Berge KE et al. Clin Genet. 2014;86:355-60; Witjas-Paalberends ER et al. Cardiovasc. Res. 2013 Aug;99(3):432-41; Chiou KR et al. J Cardiol. 2015;65:250-6; Walsh R et al. Genet Med. 2017;19:192-203). In one study, an in vitro minigene splicing assay has suggested this variant results in out-of-frame skipping of exon 18 which results in the introduction of a premature truncation codon (Millat G et al. DNA Cell Biol. 2015;34:489-96), and a second minigene assay has also suggested aberrant splicing impact (Ito K. Proc. Natl. Acad. Sci. U.S.A.. 2017 Jul;114(29):7689-7694). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Comment:
This variant changes the last nucleotide c.G of exon 18 of the MYBPC3 gene and is predicted to impair RNA splicing at the intron 18 splice donor site. Functional mini-gene assays have shown that this variant is expected to cause an out-of-frame skipping of exon 18 (PMID: 25849606, 28679633). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 22455086, 23674513, 24111713, 25086479, 25849606, 27532257, 27600940, 27885498, 29255176, 31110529, 31323898, 33495596, 33495597, 33732734, 36291626, 38757491, 25086479, 29255176, 37342443). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 25086479, 29255176, 37342443). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 37342443). This variant has been identified in 5/166884 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This is a nonsynonymous variant in the MYBPC3 gene (OMIM: 600958). Pathogenic variants in this gene have been associated with autosomal semidominant hypertrophic cardiomyopathy 4. Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.387), but functional studies have shown that this variant alters splicing and results in the skipping of exon 18 and loss of function, which is a known disease mechanism for MYBPC3 in this disorder (PMID: 28679633, 25849606) (PVS1). This variant has been reported in several affected individuals (PMID: 37652022, 27532257, 22455086, 22455086, 27532257, 31006259, 34400558) (PS4) and it has been observed to segregate with disease in at least two individuals from one family (PMID: 25086479). This variant has a 0.0176% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/) (PM2). . Based on the evidence, this variant is classified as pathogenic for autosomal dominant or autosomal recessive hypertrophic cardiomyopathy 4.
Comment:
PM2, PS3_Very Strong
Comment:
The p.Arg597Gln variant in MYBPC3 has been identified in at least 15 individuals with hypertrophic cardiomyopathy and segregated with disease in 1 affected relative (Berge 2014, Curila 2012, Chiou 2015, Millat 2015, Walsh 2016, LMM data, GeneDx pers. comm., Ambry pers comm., Invitae pers. comm., Stanford pers. comm., CHEO pers. comm, SHaRe database). The variant has been identified in 5/166884 chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant is located in the last three bases of the exon, which is part of the 5' splice region. An in vitro functional study showed that cells harboring this variant produced a shorter mRNA product than wild type cells, consistent with skipping of exon 18 (Millat 2015). Computational tools also suggest some impact to splicing. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PS3_Supporting, PP3.
Comment:
ACMG score pathogenic
Comment:
The observed missense variant, splice region c.1790G>A(p.Arg597Gln) in MYBPC3 gene has been reported previously in multiple individuals with cardiomyopathy (Cecconi M, et al., 2016, Walsh R, et al., 2017). Experimental studies have shown that this variant affects the function of the gene (Millat G, et al., 2015). 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.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Comment:
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 24 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by multiple clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from Arg to Gln. This variant impacts the last nucleotide of exon 18 and as a result may affect splicing. A minigene assay has shown abnormal splicing and skipping of exon 18 in HeLa cells (PMID: 25849606); 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); Alternative amino acid change(s) at the same position are present in gnomAD (Highest allele count: v4: 53 heterozygote(s), 0 homozygote(s)); Variant is located in the annotated immunoglobulin I-set domain (DECIPHER); Missense variant with inconclusive in silico prediction and/or uninformative conservation; 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); This variant has been shown to be maternally inherited by trio analysis.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 597 of the MYBPC3 protein (p.Arg597Gln). This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs727503195, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23674513, 24111713, 25086479, 27532257, 27600940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164098). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25849606, 28679633). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy. | Bonaventura J | Journal of the American Heart Association | 2024 | PMID: 38757491 |
| The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. | McGurk KA | American journal of human genetics | 2023 | PMID: 37652022 |
| Genetic landscape in Russian patients with familial left ventricular noncompaction. | Meshkov AN | Frontiers in cardiovascular medicine | 2023 | PMID: 37342443 |
| Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes. | Mazzaccara C | Biomolecules | 2022 | PMID: 36291626 |
| Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population. | Bourfiss M | Circulation. Genomic and precision medicine | 2022 | PMID: 36264615 |
| Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
| Sex-Related Differences in Protein Expression in Sarcomere Mutation-Positive Hypertrophic Cardiomyopathy. | Schuldt M | Frontiers in cardiovascular medicine | 2021 | PMID: 33732734 |
| Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
| Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. | Tadros R | Nature genetics | 2021 | PMID: 33495596 |
| 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 |
| Protein Quality Control Activation and Microtubule Remodeling in Hypertrophic Cardiomyopathy. | Dorsch LM | Cells | 2019 | PMID: 31323898 |
| The utility of the Mayo Score for predicting the yield of genetic testing in patients with hypertrophic cardiomyopathy. | Bonaventura J | Archives of medical science : AMS | 2019 | PMID: 31110529 |
| Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. | Norrish G | Circulation | 2019 | PMID: 31006259 |
| Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy. | Robyns T | European journal of human genetics : EJHG | 2017 | PMID: 29255176 |
| 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 |
| Prognostic predictive value of gene mutations in Japanese patients with hypertrophic cardiomyopathy. | Chida A | Heart and vessels | 2017 | PMID: 27885498 |
| 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 |
| Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy. | Cecconi M | International journal of molecular medicine | 2016 | PMID: 27600940 |
| Functional characterization of putative novel splicing mutations in the cardiomyopathy-causing genes. | Millat G | DNA and cell biology | 2015 | PMID: 25849606 |
| 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 |
| Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan. | Chiou KR | Journal of cardiology | 2015 | PMID: 25086479 |
| Genetics of hypertrophic cardiomyopathy in Norway. | Berge KE | Clinical genetics | 2014 | PMID: 24111713 |
| Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. | Witjas-Paalberends ER | Cardiovascular research | 2013 | PMID: 23674513 |
| Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy. | Curila K | Acta cardiologica | 2012 | PMID: 22455086 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Autoradiographic identification of ecdysteroid-binding cells in the nervous system of the moth Manduca sexta. | Fahrbach SE | Journal of neurobiology | 1989 | PMID: 2584960 |
| click to load more citations click to collapse | ||||
Text-mined citations for rs727503195 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 30, 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.