Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)
Germline
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.
(23)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
23
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)
Variation ID: 42735 Accession: VCV000042735.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47332189 (GRCh38) [ NCBI UCSC ] 11: 47353740 (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 Jul 8, 2016 Oct 20, 2024 Jun 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.3697C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Gln1233Ter nonsense NC_000011.10:g.47332189G>A NC_000011.9:g.47353740G>A NG_007667.1:g.25514C>T LRG_386:g.25514C>T LRG_386t1:c.3697C>T LRG_386p1:p.Gln1233Ter - Protein change
- Q1233*
- Other names
-
p.Q1233*:CAG>TAG
p.Gln1233*
- Canonical SPDI
- NC_000011.10:47332188:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 |
3959 | 3978 | |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 24, 2020 | RCV000035610.10 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2024 | RCV000158254.21 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000168193.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 4, 2015 | RCV000208463.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 28, 2017 | RCV000678715.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 9, 2021 | RCV000588073.3 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 19, 2023 | RCV001188335.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 26, 2023 | RCV003390723.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 6, 2021 | RCV002482961.2 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Dec 10, 2020 | RCV001270363.2 |
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. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jun 06, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696331.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense … (more)
Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002775432.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Apr 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059261.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, … (more)
The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner. (less)
|
|
|
Pathogenic
(Nov 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208189.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Nonsense 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 … (more)
Nonsense 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 in ClinVar (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806) (less)
|
|
|
Pathogenic
(Nov 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000264042.2
First in ClinVar: Feb 27, 2016 Last updated: Sep 22, 2018 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jul 30, 2015)
|
criteria provided, single submitter
(ACMG Guidelines, 2015)
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Center of Genomic medicine, Geneva, University Hospital of Geneva
Study: Final Reports_Cases2015_1
Accession: SCV000292232.1 First in ClinVar: Jul 08, 2016 Last updated: Jul 08, 2016 |
Comment:
This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy.
Age: 60-70 years
Sex: female
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, University of Leuven
Accession: SCV000886773.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
|
|
|
Pathogenic
(Jul 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428646.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737358.4
First in ClinVar: Mar 17, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at … (more)
The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). 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)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Region Ostergotland
Accession: SCV001984989.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
PVS1, PS4, PP5, PP1
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000218858.12
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jun 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005050617.5
First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024 |
Comment:
MYBPC3: PVS1, PP1:Strong, PS4:Moderate, PM2:Supporting, PP4
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001355372.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 08, 2022 |
Comment:
This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295). This variant has been identified in 2/249238 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)
|
|
|
Pathogenic
(Nov 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002103237.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
PP1, PM2, PS4, PVS1
|
|
|
Pathogenic
(Aug 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV002522188.2
First in ClinVar: Jun 03, 2022 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758620.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3
|
|
|
Pathogenic
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004836570.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. … (more)
This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) or referred for HCM-related genetic testing (PMID: 11499719, 16715312, 18409188, 18957093, 21302287, 22455086, 25611685, 27688314, 22515980). This variant has been reported to co-segregate with HCM in multiple families (PMID: 11499719, 16199542, 16715312, 18957093). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 10, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations
Accession: SCV001450505.1
First in ClinVar: Dec 16, 2020 Last updated: Dec 16, 2020 |
Comment:
We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic … (more)
We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic. (less)
Observation 1:
Clinical Features:
Left ventricular noncompaction cardiomyopathy (present) , Hypertrophic cardiomyopathy (present) , Supraventricular arrhythmia (present) , Atrial fibrillation (present)
Age: 30-39 years
Sex: female
Observation 2:
Clinical Features:
Hypertrophic cardiomyopathy (present) , Left ventricular noncompaction cardiomyopathy (present) , Abnormal mitral valve physiology (present) , Premature ventricular contraction (present) , Cardiac arrhythmia (present)
Age: 30-39 years
Sex: female
Comment on evidence:
The p.Q1233* variant in proband K. was observed along with the variant p.E739K in MYBPC3 gene, also heterozygous. The family was unavailable for analysis.
Observation 3:
Clinical Features:
Left ventricular noncompaction cardiomyopathy (present) , Hypertrophic cardiomyopathy (present) , Atrial fibrillation (present)
Age: 30-39 years
Sex: male
Observation 4:
Clinical Features:
Left ventricular noncompaction cardiomyopathy (present) , Ventricular tachycardia (present) , Ventricular fibrillation (present) , Arrhythmogenic Right Ventricular Dysplasia (present)
Age: 60-69 years
Sex: female
Comment on evidence:
The p.Q1233* variant in the proband I. was observed along with variant p.R237W in MYH7 gene.
|
|
|
Pathogenic
(Sep 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dilated cardiomyopathy 1I
Affected status: yes
Allele origin:
unknown
|
KardioGenetik, Herz- und Diabeteszentrum NRW
Accession: SCV004101821.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042207.2
First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 28, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Left ventricular hypertrophy
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804884.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952191.2 First in ClinVar: Oct 02, 2021 Last updated: Dec 21, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001920537.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Comment:
Comment:
The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner.
Comment:
Nonsense 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 in ClinVar (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806)
Comment:
This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy.
Comment:
The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). 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:
PVS1, PS4, PP5, PP1
Comment:
This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
MYBPC3: PVS1, PP1:Strong, PS4:Moderate, PM2:Supporting, PP4
Comment:
This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295). This variant has been identified in 2/249238 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:
PP1, PM2, PS4, PVS1
Comment:
ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3
Comment:
This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) or referred for HCM-related genetic testing (PMID: 11499719, 16715312, 18409188, 18957093, 21302287, 22455086, 25611685, 27688314, 22515980). This variant has been reported to co-segregate with HCM in multiple families (PMID: 11499719, 16199542, 16715312, 18957093). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Comment:
We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner.
Comment:
Nonsense 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 in ClinVar (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806)
Comment:
This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy.
Comment:
The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). 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:
PVS1, PS4, PP5, PP1
Comment:
This sequence change creates a premature translational stop signal (p.Gln1233*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is present in population databases (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
MYBPC3: PVS1, PP1:Strong, PS4:Moderate, PM2:Supporting, PP4
Comment:
This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295). This variant has been identified in 2/249238 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:
PP1, PM2, PS4, PVS1
Comment:
ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3
Comment:
This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) or referred for HCM-related genetic testing (PMID: 11499719, 16715312, 18409188, 18957093, 21302287, 22455086, 25611685, 27688314, 22515980). This variant has been reported to co-segregate with HCM in multiple families (PMID: 11499719, 16199542, 16715312, 18957093). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Comment:
We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
| Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
| Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. | Marschall C | Cardiovascular diagnosis and therapy | 2019 | PMID: 31737537 |
| Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
| MYBPC3 truncation mutations enhance actomyosin contractile mechanics in human hypertrophic cardiomyopathy. | O'Leary TS | Journal of molecular and cellular cardiology | 2019 | PMID: 30550750 |
| Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy. | Bagnall RD | Journal of the American College of Cardiology | 2018 | PMID: 30025578 |
| Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. | Viswanathan SK | PloS one | 2017 | PMID: 29121657 |
| Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. | Ross SB | Circulation. Cardiovascular genetics | 2017 | PMID: 28615295 |
| 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 |
| Genotype-Dependent and -Independent Calcium Signaling Dysregulation in Human Hypertrophic Cardiomyopathy. | Helms AS | Circulation | 2016 | PMID: 27688314 |
| 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 |
| Clinical application of WHF-MOGE(S) classification for hypertrophic cardiomyopathy. | Agarwal A | Global heart | 2015 | PMID: 26271555 |
| Targeted next-generation sequencing (NGS) of nine candidate genes with custom AmpliSeq in patients and a cardiomyopathy risk group. | Glotov AS | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25892673 |
| 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 |
| Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise. | Kapplinger JD | Journal of cardiovascular translational research | 2014 | PMID: 24510615 |
| Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins. | Landstrom AP | Current molecular medicine | 2012 | PMID: 22515980 |
| Spectrum and clinical manifestations of mutations in genes responsible for hypertrophic cardiomyopathy. | Curila K | Acta cardiologica | 2012 | PMID: 22455086 |
| The Gln1233ter mutation of the myosin binding protein C gene: causative mutation or innocent polymorphism in patients with hypertrophic cardiomyopathy? | Tóth T | International journal of cardiology | 2011 | PMID: 21985754 |
| A case of familial hypertrophic cardiomyopathy emphasizes the importance of parallel screening of multiple disease genes. | Scheffold T | Clinical research in cardiology : official journal of the German Cardiac Society | 2011 | PMID: 21409595 |
| Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy. | Roncarati R | Journal of cellular physiology | 2011 | PMID: 21302287 |
| 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 |
| A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy. | Fokstuen S | Human mutation | 2008 | PMID: 18409188 |
| Shared genetic causes of cardiac hypertrophy in children and adults. | Morita H | The New England journal of medicine | 2008 | PMID: 18403758 |
| Large-scale mutation screening in patients with dilated or hypertrophic cardiomyopathy: a pilot study using DGGE. | Zeller R | Journal of molecular medicine (Berlin, Germany) | 2006 | PMID: 16715312 |
| Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling. | Ingles J | Journal of medical genetics | 2005 | PMID: 16199542 |
| Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. | Van Driest SL | Journal of the American College of Cardiology | 2004 | PMID: 15519027 |
| Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy. | Erdmann J | Clinical genetics | 2003 | PMID: 12974739 |
| Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. | Erdmann J | Journal of the American College of Cardiology | 2001 | PMID: 11499719 |
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Text-mined citations for rs397516037 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.