ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.956A>C (p.Glu319Ala)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000256.3(MYBPC3):c.956A>C (p.Glu319Ala)
Variation ID: 407317 Accession: VCV000407317.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p11.2 11: 47346341 (GRCh38) [ NCBI UCSC ] 11: 47367892 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 17, 2017 Apr 20, 2024 Dec 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000256.3:c.956A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Glu319Ala missense NC_000011.10:g.47346341T>G NC_000011.9:g.47367892T>G NG_007667.1:g.11362A>C LRG_386:g.11362A>C LRG_386t1:c.956A>C LRG_386p1:p.Glu319Ala - Protein change
- E319A
- Other names
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- Canonical SPDI
- NC_000011.10:47346340:T:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00020 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00004
1000 Genomes Project 30x 0.00016
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3858 | 3875 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000463873.3 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 7, 2023 | RCV000788114.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV000845466.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 27, 2023 | RCV001188145.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 6, 2023 | RCV003168776.1 |
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
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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. |
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Uncertain significance
(Jan 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000927121.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Familial dilated cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987557.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Uncertain significance
(Nov 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003805440.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
Identified in a patient with HCM in published literature (Kassem et al., 2013); In silico analysis supports that this missense variant does not alter protein … (more)
Identified in a patient with HCM in published literature (Kassem et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23233322) (less)
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Uncertain significance
(Sep 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000546439.3
First in ClinVar: Apr 17, 2017 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 319 of the MYBPC3 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 319 of the MYBPC3 protein (p.Glu319Ala). This variant is present in population databases (rs545675333, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23233322). ClinVar contains an entry for this variant (Variation ID: 407317). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Feb 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003911310.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
The p.E319A variant (also known as c.956A>C), located in coding exon 12 of the MYBPC3 gene, results from an A to C substitution at nucleotide … (more)
The p.E319A variant (also known as c.956A>C), located in coding exon 12 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 956. The glutamic acid at codon 319 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Kassem HSh et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jun 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236665.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Uncertain significance
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001355120.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with alanine at codon 319 of the MYBPC3 protein. Computational prediction tool indicates that this variant may have a … (more)
This missense variant replaces glutamic acid with alanine at codon 319 of the MYBPC3 protein. Computational prediction tool indicates that this variant may have a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 23233322). This variant has been identified in 9/235974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Dec 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004834699.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces glutamic acid with alanine at codon 319 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein … (more)
This missense variant replaces glutamic acid with alanine at codon 319 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 23233322). This variant has been identified in 9/235974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 4
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program. | Kassem HSh | Journal of cardiovascular translational research | 2013 | PMID: 23233322 |
Text-mined citations for rs545675333 ...
HelpRecord last updated Apr 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.