This variant deletes 1 nucleotide in exon 22 in the Ig-like domain C5 of the MYBPC3 gene (also known as DelC698 and A698 fs/54 in the literature), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 15519027, 20031618, 22122802, 23549607, 24793961, 25351510, 26914223, 27532257, 28408708, 32731933, 32841044, 33495597, 34310159; Color internal data). It has been shown that this variant segregates with disease in multiple affected individuals across 2 families (PMID: 9562578, 22122802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
NC_000011.10:g.47339379del
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (14)
Pathogenic (14)
14 out of 14 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.
14
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NC_000011.10:g.47339379del
Variation ID: 42596 Accession: VCV000042596.42
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47339376 (GRCh38) [ NCBI UCSC ] 11: 47360927 (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 Dec 19, 2017 Jul 27, 2026 Apr 20, 2026 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.2096delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47339379del NC_000011.9:g.47360930del NG_007667.1:g.18327del LRG_386:g.18327del LRG_386t1:c.2096del LRG_386p1:p.Pro699fs - Protein change
- -
- Other names
-
p.Pro699Glnfs*55
- Canonical SPDI
- NC_000011.10:47339375:GGGG:GGG
-
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.
- -
- 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 |
4727 | 4749 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2026 | RCV000158358.17 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 7, 2026 | RCV000232610.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2017 | RCV000853466.2 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 20, 2026 | RCV001170424.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 31, 2022 | RCV002466417.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 7, 2023 | RCV003352753.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 05, 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: SCV005429998.1
First in ClinVar: Dec 14, 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 deletes 1 nucleotide in exon 22 in the Ig-like domain C5 of the MYBPC3 gene (also known as DelC698 and A698 fs/54 in the literature), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 15519027, 20031618, 22122802, 23549607, 24793961, 25351510, 26914223, 27532257, 28408708, 32731933, 32841044, 33495597, 34310159; Color internal data). It has been shown that this variant segregates with disease in multiple affected individuals across 2 families (PMID: 9562578, 22122802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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
|
|
|
Pathogenic
(Oct 21, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103240.2
First in ClinVar: Mar 12, 2022 Last updated: Jan 11, 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
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jan 07, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000284219.10
First in ClinVar: Jul 01, 2016 Last updated: Mar 07, 2026 |
Comment:
show
This sequence change creates a premature translational stop signal (p.Pro699Glnfs*55) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 15519027, 22122802, 24793961, 26914223). It has also been observed to segregate with disease in related individuals. This variant is also known as delC698 and A698fs/54. ClinVar contains an entry for this variant (Variation ID: 42596). 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
|
|
|
Pathogenic
(Feb 01, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV007548032.3
First in ClinVar: Apr 25, 2026 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: 1
|
|
|
Pathogenic
(Jul 13, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Blueprint Genetics
Accession: SCV000927791.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
|
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 28, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059112.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
show
The p.Pro699fs variant (also referred to as Ala698fs and A698fs54) in MYBPC3 has been reported in 8 individuals with HCM and segregated with disease in 5 affect ed family members (Nimura 1998, Van Driest 2004, Wilson 2011, Bos 2014, LMM data ). It has not been identified in large population studies. This variant is predi cted to cause a frameshift, which alters the protein?s amino acid sequence begin ning at position 699 and leads to a premature termination codon 55 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic b ased upon segregation studies, absence from controls, and the predicted impact t o the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: not provided
Number of individuals with the variant: 15
|
|
|
Pathogenic
(Nov 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000208293.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
show
Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 42596; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15114369, 25351510, 9562578, 24793961, 15519027, 22122802, 26743238, 26914223, 27532257, 28615295, 31006259, 23549607, 33087929) (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 28, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333002.3
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
(Aug 07, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiovascular phenotype |
Ambry Genetics
Accession: SCV004080085.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
show
The c.2096delC pathogenic mutation, located in coding exon 22 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 2096, causing a translational frameshift with a predicted alternate stop codon (p.P699Qfs*55). This mutation has been reported in multiple individuals and families with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Wilson MG et al. J Cardiovasc Magn Reson, 2011 Nov;13:77; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
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 31, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV005398467.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in individuals with hypertrophic cardiomyopathy (HCM) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with HCM (ClinVar, cardiodb.org, PMID: 26743238). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (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
(Aug 01, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
hypertrophic cardiomyopathy
dilated cardiomyopathy
multiple probands
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. |
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Accession: SCV000996377.3
First in ClinVar: Nov 02, 2019 Last updated: Feb 08, 2025 |
Comment:
show
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. (less)
Observation: 1
Collection method: research
Allele origin: germline
Affected status: yes
Observation 1
Collection method: research
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 07, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
Color Diagnostics, LLC DBA Color Health
Accession: SCV001735650.4
First in ClinVar: Jun 19, 2021 Last updated: May 03, 2025 |
Comment:
show
This variant deletes 1 nucleotide in exon 22 in the Ig-like domain C5 of the MYBPC3 gene (also known as DelC698 and A698 fs/54 in the literature), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 15519027, 20031618, 22122802, 23549607, 24793961, 25351510, 26914223, 27532257, 28408708, 32731933, 32841044, 33495597, 34310159, 36252119; Color internal data). It has been shown that this variant segregates with disease in multiple affected individuals across 2 families (PMID: 9562578, 22122802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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
(Apr 20, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cardiomyopathy |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV007589589.1
First in ClinVar: May 03, 2026 Last updated: May 03, 2026 |
Comment:
show
Variant summary: MYBPC3 c.2096delC (p.Pro699GlnfsX55) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 249256 control chromosomes. c.2096delC has been observed in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Murphy_2016, Van_2004, Niimura_1998, Wilson_2011, Bos_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24793961, 26914223, 9562578, 15519027, 22122802). ClinVar contains an entry for this variant (Variation ID: 42596). 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
|
|
|
Pathogenic
(Mar 15, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypertrophic cardiomyopathy 4 |
Genetics and Molecular Pathology, SA Pathology
Accession: SCV002761681.2
First in ClinVar: Dec 17, 2022 Last updated: Jul 14, 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
|
|
Comment:
Comment:
PM2_supporting, PS4, PVS1
Comment:
This sequence change creates a premature translational stop signal (p.Pro699Glnfs*55) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 15519027, 22122802, 24793961, 26914223). It has also been observed to segregate with disease in related individuals. This variant is also known as delC698 and A698fs/54. ClinVar contains an entry for this variant (Variation ID: 42596). For these reasons, this variant has been classified as Pathogenic.
Comment:
MYBPC3: PVS1, PS4:Moderate, PM2:Supporting
Comment:
The p.Pro699fs variant (also referred to as Ala698fs and A698fs54) in MYBPC3 has been reported in 8 individuals with HCM and segregated with disease in 5 affect ed family members (Nimura 1998, Van Driest 2004, Wilson 2011, Bos 2014, LMM data ). It has not been identified in large population studies. This variant is predi cted to cause a frameshift, which alters the protein?s amino acid sequence begin ning at position 699 and leads to a premature termination codon 55 amino acids d ownstream. This alteration is then predicted to lead to a truncated or absent pr otein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, this variant meets criteria to be classified as pathogenic b ased upon segregation studies, absence from controls, and the predicted impact t o the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate.
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 42596; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 15114369, 25351510, 9562578, 24793961, 15519027, 22122802, 26743238, 26914223, 27532257, 28615295, 31006259, 23549607, 33087929)
Comment:
The c.2096delC pathogenic mutation, located in coding exon 22 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 2096, causing a translational frameshift with a predicted alternate stop codon (p.P699Qfs*55). This mutation has been reported in multiple individuals and families with hypertrophic cardiomyopathy (Niimura H et al. N. Engl. J. Med., 1998 Apr;338:1248-57; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Wilson MG et al. J Cardiovasc Magn Reson, 2011 Nov;13:77; Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in individuals with hypertrophic cardiomyopathy (HCM) (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in individuals with HCM (ClinVar, cardiodb.org, PMID: 26743238). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
Comment:
This variant deletes 1 nucleotide in exon 22 in the Ig-like domain C5 of the MYBPC3 gene (also known as DelC698 and A698 fs/54 in the literature), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 15519027, 20031618, 22122802, 23549607, 24793961, 25351510, 26914223, 27532257, 28408708, 32731933, 32841044, 33495597, 34310159, 36252119; Color internal data). It has been shown that this variant segregates with disease in multiple affected individuals across 2 families (PMID: 9562578, 22122802). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Variant summary: MYBPC3 c.2096delC (p.Pro699GlnfsX55) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 249256 control chromosomes. c.2096delC has been observed in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Murphy_2016, Van_2004, Niimura_1998, Wilson_2011, Bos_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24793961, 26914223, 9562578, 15519027, 22122802). ClinVar contains an entry for this variant (Variation ID: 42596). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 Basis of Childhood Cardiomyopathy. | Bagnall RD | Circulation. Genomic and precision medicine | 2022 | PMID: 36252119 |
| A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank. | Park J | Human molecular genetics | 2022 | PMID: 34542152 |
| Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes. | Field E | Journal of medical genetics | 2022 | PMID: 34400558 |
| Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy. | de Marvao A | Journal of the American College of Cardiology | 2021 | PMID: 34503678 |
| Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers. | Hughes RK | Journal of the American Heart Association | 2021 | PMID: 34310159 |
| Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. | Harper AR | Nature genetics | 2021 | PMID: 33495597 |
| Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
| 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 |
| Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. | Lorenzini M | Journal of the American College of Cardiology | 2020 | PMID: 32731933 |
| Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. | Norrish G | Circulation | 2019 | PMID: 31006259 |
| Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. | Ingles J | Circulation. Cardiovascular genetics | 2017 | PMID: 28408708 |
| 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 |
| Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy. | Murphy SL | Journal of cardiovascular translational research | 2016 | PMID: 26914223 |
| Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. | Adler A | Circulation. Arrhythmia and electrophysiology | 2016 | PMID: 26743238 |
| 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 |
| Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
| Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy. | Bos JM | Mayo Clinic proceedings | 2014 | PMID: 24793961 |
| T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy. | Ho CY | Circulation. Cardiovascular imaging | 2013 | PMID: 23549607 |
| Hypertrophic cardiomyopathy and ultra-endurance running - two incompatible entities? | Wilson MG | Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance | 2011 | PMID: 22122802 |
| Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy. | Kaski JP | Circulation. Cardiovascular genetics | 2009 | PMID: 20031618 |
| Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
| 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 |
| 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 |
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Text-mined citations for rs397515947 ...
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Record last updated Jul 27, 2026
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