VCV000521502.6 - ClinVar

NM_015100.4(POGZ):c.4103_4104inv (p.Thr1368Lys)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015100.4(POGZ):c.4103_4104inv (p.Thr1368Lys)

Variation ID: 521502 Accession: VCV000521502.6

Type and length

Inversion, 2 bp

Location

Cytogenetic: 1q21.3 1: 151404931-151404932 (GRCh38) [ NCBI UCSC ] 1: 151377407-151377408 (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	Apr 15, 2018	May 1, 2024	May 8, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_015100.4:c.4103_4104inv MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055915.2:p.Thr1368Lys	missense
NM_001194937.2:c.4076_4077inv	NP_001181866.1:p.Thr1359Lys	missense
NM_001194938.2:c.3917_3918inv	NP_001181867.1:p.Thr1306Lys	missense
NM_145796.4:c.3818_3819inv	NP_665739.3:p.Thr1273Lys	missense
NM_207171.2:c.3944_3945inv	NP_997054.1:p.Thr1315Lys	missense
NC_000001.11:g.151404931_151404932inv
NC_000001.10:g.151377407_151377408inv
NG_046601.1:g.59534_59535inv

... more HGVS ... less HGVS

Protein change

T1306K, T1315K, T1368K, T1273K, T1359K

Other names

Canonical SPDI

NC_000001.11:151404930:AG:CT

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: CA658795512 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.
POGZ		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	673	691

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.
Inborn genetic diseases	Uncertain significance (2)	criteria provided, single submitter	May 8, 2017	RCV000623084.11

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.
Uncertain significance (Mar 16, 2017)	criteria provided, single submitter (ambry_reporting_categories_2017) Method: clinical testing	Hereditary disease Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742122.2 First in ClinVar: Apr 15, 2018 Last updated: Dec 11, 2022	Publications: PubMed (13) PubMed: 24267886‚ 22542183‚ 22495311‚ 24463507‚ 24896178‚ 23375656‚ 25533962‚ 25694107‚ 26739615‚ 26942287‚ 27148570‚ 9862965‚ 28480548 Comment: Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected Clinical Features: MR/ID/DD (present) , Autism spectrum (present) , Psychiatric (present) , Dysmorphic features (present) , Genitourinary (child onset) (present) , Musculoskeletal/Structural (child onset) (present) , Neurologic … (more) MR/ID/DD (present) , Autism spectrum (present) , Psychiatric (present) , Dysmorphic features (present) , Genitourinary (child onset) (present) , Musculoskeletal/Structural (child onset) (present) , Neurologic (child onset) (present) (less) Zygosity: Single Heterozygote Family history: yes Sex: male Segregation observed: yes
Uncertain significance (May 08, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000848723.5 First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024	Comment: The c.4103_4104delinsAG variant, also known as p.T1368K, is located in coding exon 18 of the POGZ gene, results from an in-frame deletion of CT and … (more) The c.4103_4104delinsAG variant, also known as p.T1368K, is located in coding exon 18 of the POGZ gene, results from an in-frame deletion of CT and insertion of AG at nucleotide positions 4103 to 4104. This results in the substitution of the threonine residue for a lysine residue at codon 1368, an amino acid with similar properties. This amino acid positions are not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The c.4103_4104delinsAG variant, also known as p.T1368K, is located in coding exon 18 of the POGZ gene, results from an in-frame deletion of CT and insertion of AG at nucleotide positions 4103 to 4104. This results in the substitution of the threonine residue for a lysine residue at codon 1368, an amino acid with similar properties. This amino acid positions are not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Expanding the phenotypic spectrum of truncating POGZ mutations: Association with CNS malformations, skeletal abnormalities, and distinctive facial dysmorphism.	Dentici ML	American journal of medical genetics. Part A	2017	PMID: 28480548
Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.	Stessman HAF	American journal of human genetics	2016	PMID: 26942287
POGZ truncating alleles cause syndromic intellectual disability.	White J	Genome medicine	2016	PMID: 26739615
De novo POGZ mutations are associated with neurodevelopmental disorders and microcephaly.	Ye Y	Cold Spring Harbor molecular case studies	2015	PMID: 27148570
A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.	Fukai R	Journal of human genetics	2015	PMID: 25694107
Large-scale discovery of novel genetic causes of developmental disorders.	Deciphering Developmental Disorders Study	Nature	2015	PMID: 25533962
Genome sequencing identifies major causes of severe intellectual disability.	Gilissen C	Nature	2014	PMID: 24896178
De novo mutations in schizophrenia implicate synaptic networks.	Fromer M	Nature	2014	PMID: 24463507
Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.	Willsey AJ	Cell	2013	PMID: 24267886
Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder.	Girirajan S	American journal of human genetics	2013	PMID: 23375656
De novo gene disruptions in children on the autistic spectrum.	Iossifov I	Neuron	2012	PMID: 22542183
Patterns and rates of exonic de novo mutations in autism spectrum disorders.	Neale BM	Nature	2012	PMID: 22495311
Pogo transposase contains a putative helix-turn-helix DNA binding domain that recognises a 12 bp sequence within the terminal inverted repeats.	Wang H	Nucleic acids research	1999	PMID: 9862965
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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_015100.4(POGZ):c.4103_4104inv (p.Thr1368Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...