This sequence change creates a premature translational stop signal (p.Arg417*) in the UBE3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UBE3A are known to be pathogenic (PMID: 25212744). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Angelman syndrome (PMID: 8988172). ClinVar contains an entry for this variant (Variation ID: 7966). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_130839.5(UBE3A):c.1309C>T (p.Arg437Ter)
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.
(4)
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
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_130839.5(UBE3A):c.1309C>T (p.Arg437Ter)
Variation ID: 7966 Accession: VCV000007966.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q11.2 15: 25370865 (GRCh38) [ NCBI UCSC ] 15: 25616012 (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 Mar 18, 2018 Feb 14, 2024 Jul 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_130839.5:c.1309C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_570854.1:p.Arg437Ter nonsense NM_000462.5:c.1318C>T NP_000453.2:p.Arg440Ter nonsense NM_001354505.1:c.1309C>T NP_001341434.1:p.Arg437Ter nonsense NM_001354506.2:c.1249C>T NP_001341435.1:p.Arg417Ter nonsense NM_001354507.2:c.1249C>T NP_001341436.1:p.Arg417Ter nonsense NM_001354508.2:c.1249C>T NP_001341437.1:p.Arg417Ter nonsense NM_001354509.2:c.1249C>T NP_001341438.1:p.Arg417Ter nonsense NM_001354511.2:c.1249C>T NP_001341440.1:p.Arg417Ter nonsense NM_001354512.2:c.1249C>T NP_001341441.1:p.Arg417Ter nonsense NM_001354513.2:c.1249C>T NP_001341442.1:p.Arg417Ter nonsense NM_001354523.2:c.1249C>T NP_001341452.1:p.Arg417Ter nonsense NM_001354526.1:c.1249C>T NP_001341455.1:p.Arg417Ter nonsense NM_001354538.2:c.1309C>T NP_001341467.1:p.Arg437Ter nonsense NM_001354539.2:c.1249C>T NP_001341468.1:p.Arg417Ter nonsense NM_001354540.2:c.1249C>T NP_001341469.1:p.Arg417Ter nonsense NM_001354541.2:c.1249C>T NP_001341470.1:p.Arg417Ter nonsense NM_001354542.2:c.1249C>T NP_001341471.1:p.Arg417Ter nonsense NM_001354543.2:c.1249C>T NP_001341472.1:p.Arg417Ter nonsense NM_001354544.2:c.1249C>T NP_001341473.1:p.Arg417Ter nonsense NM_001354545.2:c.1309C>T NP_001341474.1:p.Arg437Ter nonsense NM_001354546.2:c.1132C>T NP_001341475.1:p.Arg378Ter nonsense NM_001354547.2:c.1249C>T NP_001341476.1:p.Arg417Ter nonsense NM_001354548.2:c.1249C>T NP_001341477.1:p.Arg417Ter nonsense NM_001354549.2:c.1249C>T NP_001341478.1:p.Arg417Ter nonsense NM_001354550.2:c.361+4600C>T intron variant NM_001354551.2:c.301+4600C>T intron variant NM_001374461.1:c.1249C>T NP_001361390.1:p.Arg417Ter nonsense NM_130838.4:c.1249C>T NP_570853.1:p.Arg417Ter nonsense NR_148916.2:n.1825C>T non-coding transcript variant NC_000015.10:g.25370865G>A NC_000015.9:g.25616012G>A NG_009268.1:g.73117C>T LRG_15:g.73117C>T - Protein change
- R417*, R440*, R378*, R437*
- Other names
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- Canonical SPDI
- NC_000015.10:25370864:G:A
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
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| UBE3A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
40 | 1230 | |
| SNHG14 | - | - | GRCh38 | 4 | 1129 | |
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
|
Jul 27, 2023 | RCV000008430.11 |
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. |
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Pathogenic
(Dec 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Angelman syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV000890113.1
First in ClinVar: Mar 18, 2018 Last updated: Mar 18, 2018 |
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Pathogenic
(Jul 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Angelman syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002242047.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg417*) in the UBE3A gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg417*) in the UBE3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UBE3A are known to be pathogenic (PMID: 25212744). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Angelman syndrome (PMID: 8988172). ClinVar contains an entry for this variant (Variation ID: 7966). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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ANGELMAN SYNDROME
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046078.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant is also referred to as c.1249C>T (p.Arg417Ter) in the literature. This nonsense variant found in exon 4 of 11 is predicted to result … (more)
This variant is also referred to as c.1249C>T (p.Arg417Ter) in the literature. This nonsense variant found in exon 4 of 11 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in a patient with Angelman syndrome (PMID: 8988172). Loss-of-function splicing variation in UBE3A is an established mechanism of disease (PMID: 20301323). This variant results in loss of a TaqI restriction enzyme site (PMID: 8988172). The c.1318C>T (p.Arg440Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1318C>T (p.Arg440Ter) variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 1997)
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no assertion criteria provided
Method: literature only
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ANGELMAN SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028638.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 24, 2022 |
Comment on evidence:
In a patient with Angelman syndrome (AS; 105830), Matsuura et al. (1997) identified an arg417-to-ter (R417X) nonsense mutation. This mutation resulted in loss of a … (more)
In a patient with Angelman syndrome (AS; 105830), Matsuura et al. (1997) identified an arg417-to-ter (R417X) nonsense mutation. This mutation resulted in loss of a TaqI restriction enzyme site. An analysis of the family revealed that this was a de novo mutation. (less)
|
Comment:
Comment:
This variant is also referred to as c.1249C>T (p.Arg417Ter) in the literature. This nonsense variant found in exon 4 of 11 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in a patient with Angelman syndrome (PMID: 8988172). Loss-of-function splicing variation in UBE3A is an established mechanism of disease (PMID: 20301323). This variant results in loss of a TaqI restriction enzyme site (PMID: 8988172). The c.1318C>T (p.Arg440Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1318C>T (p.Arg440Ter) variant is 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:
This sequence change creates a premature translational stop signal (p.Arg417*) in the UBE3A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UBE3A are known to be pathogenic (PMID: 25212744). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Angelman syndrome (PMID: 8988172). ClinVar contains an entry for this variant (Variation ID: 7966). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is also referred to as c.1249C>T (p.Arg417Ter) in the literature. This nonsense variant found in exon 4 of 11 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in a patient with Angelman syndrome (PMID: 8988172). Loss-of-function splicing variation in UBE3A is an established mechanism of disease (PMID: 20301323). This variant results in loss of a TaqI restriction enzyme site (PMID: 8988172). The c.1318C>T (p.Arg440Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1318C>T (p.Arg440Ter) variant is classified as Pathogenic.
Citations for germline classification of this variant
HelpText-mined citations for this variant ...
HelpRecord last updated Sep 29, 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.