The 3491-2A>T variant (MYBPC3) has been identified in three individuals with HCM tested by our laboratory. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. Heterozygous loss of function of the MYBP C3 gene is an established disease mechanism in HCM. In summary, this variant mee ts our criteria for pathogenicity (http://pcpgm.partners.org/LMM).
ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3491-2A>T
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.
(8)
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
8
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.3491-2A>T
Variation ID: 42717 Accession: VCV000042717.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47332704 (GRCh38) [ NCBI UCSC ] 11: 47354255 (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 Jun 1, 2016 Oct 26, 2024 Oct 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000256.3:c.3491-2A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000011.10:g.47332704T>A NC_000011.9:g.47354255T>A NG_007667.1:g.24999A>T LRG_386:g.24999A>T LRG_386t1:c.3491-2A>T - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000011.10:47332703:T: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.
-
The Genome Aggregation Database (gnomAD) 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 |
3971 | 3990 | |
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
|
Oct 8, 2024 | RCV000443859.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 29, 2023 | RCV000464319.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 12, 2023 | RCV003314558.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 8, 2023 | RCV003333007.1 |
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. |
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
(May 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Left ventricular noncompaction 10
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004040665.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(May 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004041117.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Apr 18, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059243.5
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Comment:
The 3491-2A>T variant (MYBPC3) has been identified in three individuals with HCM tested by our laboratory. This variant occurs in the invariant region (+/- 1,2) … (more)
The 3491-2A>T variant (MYBPC3) has been identified in three individuals with HCM tested by our laboratory. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. Heterozygous loss of function of the MYBP C3 gene is an established disease mechanism in HCM. In summary, this variant mee ts our criteria for pathogenicity (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 3
|
|
|
Pathogenic
(May 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 4
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004014666.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The MYBPC3 c.3491-2A>T variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. This variant has been reported … (more)
The MYBPC3 c.3491-2A>T variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. This variant has been reported in at least five unrelated individuals with hypertrophic cardiomyopathy (PMID: 25611685; PMID: 30282064; PMID: 31006259). This variant has been classified as pathogenic by at least three submitters in ClinVar. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, other substitutions at this same splice acceptor junction, such as c.3491-1G>A and c.3491-3C>G, have been reported in other patients with hypertrophic cardiomyopathy (PMID: 23283745; PMID: 30645170). Based on the available evidence, the c.3491-2A>T variant is classified as pathogenic for hypertrophic cardiomyopathy. (less)
|
|
|
Likely pathogenic
(Oct 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000516855.6
First in ClinVar: Mar 08, 2017 Last updated: Oct 26, 2024 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 31006259, 37652022, 25611685, 30282064) (less)
|
|
|
Pathogenic
(Nov 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000546428.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 25611685, 27532257, 30282064). ClinVar contains an entry for this variant (Variation ID: 42717). 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)
|
|
|
Likely pathogenic
(Nov 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433206.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
|
|
|
Pathogenic
(Aug 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503531.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
Comment:
Comment:
The MYBPC3 c.3491-2A>T variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. This variant has been reported in at least five unrelated individuals with hypertrophic cardiomyopathy (PMID: 25611685; PMID: 30282064; PMID: 31006259). This variant has been classified as pathogenic by at least three submitters in ClinVar. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, other substitutions at this same splice acceptor junction, such as c.3491-1G>A and c.3491-3C>G, have been reported in other patients with hypertrophic cardiomyopathy (PMID: 23283745; PMID: 30645170). Based on the available evidence, the c.3491-2A>T variant is classified as pathogenic for hypertrophic cardiomyopathy.
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 31006259, 37652022, 25611685, 30282064)
Comment:
This sequence change affects an acceptor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 25611685, 27532257, 30282064). ClinVar contains an entry for this variant (Variation ID: 42717). 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.
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:
The 3491-2A>T variant (MYBPC3) has been identified in three individuals with HCM tested by our laboratory. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing lea ding to an abnormal or absent protein. Heterozygous loss of function of the MYBP C3 gene is an established disease mechanism in HCM. In summary, this variant mee ts our criteria for pathogenicity (http://pcpgm.partners.org/LMM).
Comment:
The MYBPC3 c.3491-2A>T variant results in a substitution at the consensus splice acceptor site, which may result in splicing defects. This variant has been reported in at least five unrelated individuals with hypertrophic cardiomyopathy (PMID: 25611685; PMID: 30282064; PMID: 31006259). This variant has been classified as pathogenic by at least three submitters in ClinVar. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Additionally, other substitutions at this same splice acceptor junction, such as c.3491-1G>A and c.3491-3C>G, have been reported in other patients with hypertrophic cardiomyopathy (PMID: 23283745; PMID: 30645170). Based on the available evidence, the c.3491-2A>T variant is classified as pathogenic for hypertrophic cardiomyopathy.
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 31006259, 37652022, 25611685, 30282064)
Comment:
This sequence change affects an acceptor splice site in intron 31 of the MYBPC3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 25611685, 27532257, 30282064). ClinVar contains an entry for this variant (Variation ID: 42717). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Yield of Clinical Screening for Hypertrophic Cardiomyopathy in Child First-Degree Relatives. | Norrish G | Circulation | 2019 | PMID: 31006259 |
| Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy. | Singer ES | Circulation. Genomic and precision medicine | 2019 | PMID: 30645170 |
| Phenotypic variations in carriers of predicted protein-truncating genetic variants in MYBPC3: an autopsy-based case series. | Williams N | Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology | 2018 | PMID: 30282064 |
| 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 |
| 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 |
| Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. | Zou Y | Molecular biology reports | 2013 | PMID: 23283745 |
| Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. | Marston S | Circulation research | 2009 | PMID: 19574547 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs397516022 ...
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 Oct 27, 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.