NM_015100.4(POGZ):c.3118G>A (p.Glu1040Lys) AND Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 1, 2024
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:: RCV004555898.1

Allele description [Variation Report for NM_015100.4(POGZ):c.3118G>A (p.Glu1040Lys)]

NM_015100.4(POGZ):c.3118G>A (p.Glu1040Lys)

Gene:

POGZ:pogo transposable element derived with ZNF domain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q21.3

Genomic location:

Preferred name:

NM_015100.4(POGZ):c.3118G>A (p.Glu1040Lys)

HGVS:

NC_000001.11:g.151405917C>T
NG_046601.1:g.58549G>A
NM_001194937.2:c.3091G>A
NM_001194938.2:c.2932G>A
NM_015100.4:c.3118G>AMANE SELECT
NM_145796.4:c.2833G>A
NM_207171.2:c.2959G>A
NP_001181866.1:p.Glu1031Lys
NP_001181867.1:p.Glu978Lys
NP_055915.2:p.Glu1040Lys
NP_665739.3:p.Glu945Lys
NP_997054.1:p.Glu987Lys
NC_000001.10:g.151378393C>T
NM_015100.3:c.3118G>A

Protein change:

E1031K

Links:

dbSNP: rs2102146729

NCBI 1000 Genomes Browser:

rs2102146729

Molecular consequence:

NM_001194937.2:c.3091G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001194938.2:c.2932G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_015100.4:c.3118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_145796.4:c.2833G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_207171.2:c.2959G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
Identifiers:: MONDO: MONDO:0014606; MedGen: C4225351; OMIM: 616364

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Transmembrane protein 205-like [Crotalus adamanteus]
Transmembrane protein 205-like [Crotalus adamanteus]
gi|387019271|gb|AFJ51753.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005045043	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 1, 2024)	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

SCV005045043

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 1, 2024)

germline

clinical testing

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

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Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV005045043.1

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

Description

The POGZ c.3118G>A (p.Glu1040Lys) variant has been reported in at least five individuals affected with White-Sutton syndrome or autism and is occurred de novo in at least four individuals (1, 5, 6, 7, 8). This variant has been reported in the ClinVar database as a germline pathogenic variant by one submitter. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors are uncertain on the impact of this variant on POGZ function. Functional studies show conflicting results: at least one study indicates this variant may alter cellular localization (1) while another study indicates the variant does not alter localization and can rescue phenotype similar to the native protein (9). Based on available information and the ACMG/AMP guidelines for variant interpretation (10), this variant is classified as pathogenic.

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

Last Updated: May 26, 2024

ClinVar

Relating variation to medicine