VCV000155982.2 - ClinVar

NM_130839.5(UBE3A):c.2557_2560dup (p.Lys854fs)

Germline

Classification

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.

(2)

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

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_130839.5(UBE3A):c.2557_2560dup (p.Lys854fs)

Variation ID: 155982 Accession: VCV000155982.2

Type and length

Duplication, 4 bp

Location

Cytogenetic: 15q11.2 15: 25339195-25339196 (GRCh38) [ NCBI UCSC ] 15: 25584342-25584343 (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	Oct 4, 2014	Feb 14, 2024	Nov 18, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_130839.5:c.2557_2560dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_570854.1:p.Lys854fs	frameshift
NM_000462.5:c.2566_2569dup	NP_000453.2:p.Lys857fs	frameshift
NM_001354505.1:c.2557_2560dup	NP_001341434.1:p.Lys854fs	frameshift
NM_001354506.2:c.2497_2500dup	NP_001341435.1:p.Lys834fs	frameshift
NM_001354507.2:c.2497_2500dup	NP_001341436.1:p.Lys834fs	frameshift
NM_001354508.2:c.2497_2500dup	NP_001341437.1:p.Lys834fs	frameshift
NM_001354509.2:c.2497_2500dup	NP_001341438.1:p.Lys834fs	frameshift
NM_001354511.2:c.2497_2500dup	NP_001341440.1:p.Lys834fs	frameshift
NM_001354512.2:c.2497_2500dup	NP_001341441.1:p.Lys834fs	frameshift
NM_001354513.2:c.2497_2500dup	NP_001341442.1:p.Lys834fs	frameshift
NM_001354523.2:c.2497_2500dup	NP_001341452.1:p.Lys834fs	frameshift
NM_001354526.1:c.2497_2500dup	NP_001341455.1:p.Lys834fs	frameshift
NM_001354538.2:c.2557_2560dup	NP_001341467.1:p.Lys854fs	frameshift
NM_001354539.2:c.2497_2500dup	NP_001341468.1:p.Lys834fs	frameshift
NM_001354540.2:c.2497_2500dup	NP_001341469.1:p.Lys834fs	frameshift
NM_001354541.2:c.2497_2500dup	NP_001341470.1:p.Lys834fs	frameshift
NM_001354542.2:c.2497_2500dup	NP_001341471.1:p.Lys834fs	frameshift
NM_001354543.2:c.2497_2500dup	NP_001341472.1:p.Lys834fs	frameshift
NM_001354544.2:c.2497_2500dup	NP_001341473.1:p.Lys834fs	frameshift
NM_001354545.2:c.2401_2404dup	NP_001341474.1:p.Lys802fs	frameshift
NM_001354546.2:c.2380_2383dup	NP_001341475.1:p.Lys795fs	frameshift
NM_001354547.2:c.2341_2344dup	NP_001341476.1:p.Lys782fs	frameshift
NM_001354548.2:c.2341_2344dup	NP_001341477.1:p.Lys782fs	frameshift
NM_001354549.2:c.2332_2335dup	NP_001341478.1:p.Lys779fs	frameshift
NM_001354550.2:c.1306_1309dup	NP_001341479.1:p.Lys437fs	frameshift
NM_001354551.2:c.1246_1249dup	NP_001341480.1:p.Lys417fs	frameshift
NM_001374461.1:c.2497_2500dup	NP_001361390.1:p.Lys834fs	frameshift
NM_130838.4:c.2497_2500dup	NP_570853.1:p.Lys834fs	frameshift
NR_148916.2:n.3069_3072dup		non-coding transcript variant
NC_000015.10:g.25339199_25339202dup
NC_000015.9:g.25584346_25584349dup
NG_009268.1:g.104783_104786dup
LRG_15:g.104783_104786dup

... more HGVS ... less HGVS

Protein change

K437fs, K779fs, K854fs, K795fs, K834fs, K857fs, K417fs, K782fs, K802fs

Other names

Canonical SPDI

NC_000015.10:25339195:TTTCTTT:TTTCTTTCTTT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA333363 dbSNP: rs587781229 VarSome

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
Gene	OMIM	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.
UBE3A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	40	1243
SNHG14		-	-	GRCh38	4	1147

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.
Angelman syndrome	Pathogenic (2)	criteria provided, single submitter	Nov 18, 2022	RCV000144305.4

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 (Nov 18, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Angelman syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004297178.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 11748306‚ 20034088‚ 25212744 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the UBE3A protein in which other variant(s) (p.Glu837Argfs4) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the UBE3A protein in which other variant(s) (p.Glu837Argfs4) have been determined to be pathogenic (PMID: 11748306, 20034088). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 155982). This premature translational stop signal has been observed in individual(s) with clinical features of UBE3A-related conditions (PMID: 25212744). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys834Argfs*4) in the UBE3A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the UBE3A protein. (less)
Pathogenic (Feb 14, 2014)	no assertion criteria provided Method: clinical testing	Angelman Syndrome Affected status: yes Allele origin: germline	Baylor Genetics Study: UBE3A Mutation Study Accession: SCV000172056.1 First in ClinVar: Oct 04, 2014 Last updated: Oct 04, 2014 Comment: Data collected from clinical UBE3A sequence analysis results	Publications: PubMed (1) PubMed: 25212744 Number of individuals with the variant: 1

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the UBE3A protein in which other variant(s) (p.Glu837Argfs*4) have been determined to be pathogenic (PMID: 11748306, 20034088). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 155982). This premature translational stop signal has been observed in individual(s) with clinical features of UBE3A-related conditions (PMID: 25212744). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys834Argfs*4) in the UBE3A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the UBE3A protein.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutation Update for UBE3A variants in Angelman syndrome.	Sadikovic B	Human mutation	2014	PMID: 25212744
A novel UBE3A truncating mutation in large Tunisian Angelman syndrome pedigree.	Abaied L	American journal of medical genetics. Part A	2010	PMID: 20034088
Distinct phenotypes distinguish the molecular classes of Angelman syndrome.	Lossie AC	Journal of medical genetics	2001	PMID: 11748306

Text-mined citations for rs587781229 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_130839.5(UBE3A):c.2557_2560dup (p.Lys854fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587781229 ...