SZT2

protein-coding

SZT2 subunit of KICSTOR complex, the group of MicroRNA protein coding host genes|KICSTOR complex

Gene summary

The protein encoded by this gene is expressed in the brain, predominantly in the parietal and frontal cortex as well as in dorsal root ganglia. It is localized to the peroxisome, and is implicated in resistance to oxidative stress. It likely functions by increasing superoxide dismutase (SOD) activity, but itself has no direct SOD activity. Studies in mice show that this gene confers low seizure threshold, and may also enhance epileptogenesis. [provided by RefSeq, Jun 2011]

Previous symbols:

C1orf84
KIAA0467

MANE transcript

NM_001365999.1

Inheritance

AR, AD

ClinVar variants

P:201U:1615B:997

Top phenotype

Developmental and epileptic encephalopathy 18

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr1:43,389,882-43,454,247

External References & Databases

Ensembl (ENSG00000198198)

Transcript & Mutation Effects

hg38 • Region Span ~64.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014201

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014201

Submitter: G2P

developmental and epileptic encephalopathy, 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014201

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 18DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014201

Submitter: Illumina

developmental and epileptic encephalopathy, 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014201

Submitter: Ambry Genetics

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: ClinGen

The *SZT2* gene was first identified in 2009 in mice with reduced seizure threshold (Frankel et al., PMID:19624305). Later, in 2013, Basel-Vanagaite et al reported biallelic variants in patients with infantile encephalopathy with epilepsy and dysmorphic corpus callosum (PMID:23932106). More recently, *SZT2* was revealed to play an important role in a novel protein complex called KICSTOR, a negative regulator of the mTOR pathway. Variants in SZT2 may lead to elevated mTorc1 signaling (PMIDs:28199306, 28199315). Clinical features in individuals with biallelic variants in *SZT2* include infantile- to early-onset epilepsy (onset within 1 day to 10 years), intellectual disability, developmental delay, macrocephaly with dysmorphic facial features, dysmorphic corpus callosum and dysregulated cortical migration. At least 13 unique variants reported in 7 probands were included in this curation (PMIDs: 23932106, 27248490, 28556953, 29696782, 30818181). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by experimental evidence including a mouse model (PMID:19624305). In summary, *SZT2* is definitively associated with autosomal recessive developmental and epileptic encephalopathy. This classification was approved by the Epilepsy Gene Curation Expert Panel on 02/02/2021 (SOP version 8).

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 18AR

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 21835308; 23932106

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SZT2 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 3233

Inborn genetic diseasesTotal: 754

Developmental and epileptic encephalopathy, 18Total: 634

not specifiedTotal: 277

SZT2-related disorderTotal: 112

Self-limited epilepsy with centrotemporal spikesTotal: 11

See casesTotal: 3

EncephaloceleTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001365999.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			20 clinvar	915 clinvar	2 clinvar	937
missense	7 clinvar	10 clinvar	1575 clinvar	74 clinvar	5 clinvar	1671
nonsense	44 clinvar	24 clinvar	1 clinvar			69
start loss						0
frameshift	62 clinvar	15 clinvar	5 clinvar			82
splice donor/acceptor (+/-2bp)	3 clinvar	36 clinvar	14 clinvar	1 clinvar		54
Total	116	85	1615	990	7	2813

Highest pathogenic variant AF is 0.000047088623

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001365999.1	RefSeq	NP_001352928.1	72	MANE Select
ENST00000634258.3	Ensembl	ENSP00000489255.1	72	MANE Select
NM_015284.4	RefSeq	NP_056099.3	71	Standard
ENST00000372450.8	Ensembl	ENSP00000361528.4	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

central nervous system development
post-embryonic development
corpus callosum morphogenesis
cellular response to amino acid starvation
cellular response to glucose starvation

Molecular Function

molecular_function
protein binding

Cellular Component

lysosomal membrane
peroxisome
GATOR2 complex
KICSTOR complex
GATOR1 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000562955
Coding exons: 71
Length: 62769
Individuals with no LoFs: 125598
Homozygous LoFs: 0
Heterozygous LoFs: 150
Defined: 125748
p: 0.000597

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.60	1666	1.99e+3	0.836	0.000126	21596
Missense (PolyPhen)		719	957.36	0.75102		10436
Synonymous	0.228	768	776	0.990	0.0000437	7211
Loss of Function	8.52	61	187	0.327	0.0000117	1842

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00064	0.00062	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00022	0.00020	rare
East Asian	0.00088	0.00087	rare
Finnish	0.00031	0.00023	rare
European (Non-Finnish)	0.00069	0.00067	rare
South Asian	0.0010	0.0010	notable
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: As part of the KICSTOR complex functions in the amino acid-sensing branch of the TORC1 signaling pathway. Recruits, in an amino acid-independent manner, the GATOR1 complex to the lysosomal membranes and allows its interaction with GATOR2 and the RAG GTPases. Functions upstream of the RAG GTPases and is required to negatively regulate mTORC1 signaling in absence of amino acids. In absence of the KICSTOR complex mTORC1 is constitutively localized to the lysosome and activated. The KICSTOR complex is also probably involved in the regulation of mTORC1 by glucose (PubMed:28199306, PubMed:28199315). May play a role in the cellular response to oxidative stress (By similarity). {ECO:0000250|UniProtKB:A2A9C3, ECO:0000269|PubMed:28199306, ECO:0000269|PubMed:28199315}.;

Recessive Scores

pRec: 0.0920

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium