NM_004456.5(EZH2):c.2218_2220dup (p.Lys740dup) AND Weaver syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 9, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000699921.3

Allele description [Variation Report for NM_004456.5(EZH2):c.2218_2220dup (p.Lys740dup)]

NM_004456.5(EZH2):c.2218_2220dup (p.Lys740dup)

Gene:

EZH2:enhancer of zeste 2 polycomb repressive complex 2 subunit [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

7q36.1

Genomic location:

Preferred name:

NM_004456.5(EZH2):c.2218_2220dup (p.Lys740dup)

HGVS:

NC_000007.14:g.148807683_148807685dup
NG_032043.1:g.81666_81668dup
NM_001203247.2:c.2203_2205dup
NM_001203248.2:c.2176_2178dup
NM_001203249.2:c.2050_2052dup
NM_004456.5:c.2218_2220dupMANE SELECT
NM_152998.3:c.2086_2088dup
NP_001190176.1:p.Lys735dup
NP_001190177.1:p.Lys726dup
NP_001190178.1:p.Lys684dup
NP_004447.2:p.Lys740dup
NP_694543.1:p.Lys696dup
LRG_531:g.81666_81668dup
NC_000007.13:g.148504775_148504777dup
NM_004456.4:c.2218_2220dupAAG

Links:

dbSNP: rs1563181659

NCBI 1000 Genomes Browser:

rs1563181659

Molecular consequence:

NM_001203247.2:c.2203_2205dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001203248.2:c.2176_2178dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_001203249.2:c.2050_2052dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_004456.5:c.2218_2220dup - inframe_insertion - [Sequence Ontology: SO:0001821]
NM_152998.3:c.2086_2088dup - inframe_insertion - [Sequence Ontology: SO:0001821]

Condition(s)

Name:: Weaver syndrome (WVS)
Synonyms:: Weaver Smith syndrome; Overgrowth syndrome with accelerated skeletal maturation, unusual facies, and camptodactyly
Identifiers:: MONDO: MONDO:0010193; MedGen: C0265210; Orphanet: 3447; OMIM: 277590

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RecName: Full=Phosphorylase b kinase regulatory subunit alpha, liver isoform; Sh...
RecName: Full=Phosphorylase b kinase regulatory subunit alpha, liver isoform; Short=Phosphorylase kinase alpha L subunit
gi|1170685|sp|P46019.1|KPB2_HUMAN

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828652	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 9, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000828652

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 9, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828652.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant, c.2218_2220dupAAG, results in the insertion of 1 amino acid(s) to the EZH2 protein (p.Lys740dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with overgrowth, developmental delay and advanced bone age (Invitae). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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