SQSTM1

sequestosome 1, the group of Zinc fingers ZZ-type

Basic information

Region (hg38): 5:179806398-179838078

Previous symbols: [ "PDB3", "OSIL" ]

Links

ENSG00000161011 ∙ NCBI:8878 ∙ OMIM:601530 ∙ HGNC:11280 ∙ Uniprot:Q13501 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
• behavioral variant of frontotemporal dementia (Supportive), mode of inheritance: AD
• frontotemporal dementia with motor neuron disease (Supportive), mode of inheritance: AD
• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (Definitive), mode of inheritance: AR
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (Strong), mode of inheritance: AD
• Paget disease of bone 3 (Strong), mode of inheritance: AD
• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (Strong), mode of inheritance: AR
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (Moderate), mode of inheritance: AD
• osteosarcoma (Strong), mode of inheritance: AD
• Paget disease of bone 3 (Strong), mode of inheritance: AD
• frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (Strong), mode of inheritance: AD
• neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Paget disease of bone 3	AD	Musculoskeletal; Oncologic	Medical management (eg, inhibitors of osteoclastic bone resorption) can be beneficial - bisphosphonates are the current first line of treatment; Awareness of the risk of related oncologic processes (eg, osteosarcoma) may be beneficial to allow early treatment	Audiologic/Otolaryngologic; Musculoskeletal; Neurologic; Oncologic	9626117; 11123042; 12374763; 11992264; 15176995; 18620951; 21735147; 22024254; 22084127; 22972638; 24042580; 24486447; 26208961; 27545679

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SQSTM1 gene.

• Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Paget disease of bone 2, early-onset (14 variants)
• Paget disease of bone 2, early-onset;Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (9 variants)
• Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (3 variants)
• not provided (3 variants)
• Paget disease of bone 3 (1 variants)
• Myopathy, distal, with rimmed vacuoles (1 variants)
• SQSTM1-related disorder (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SQSTM1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	141	5	148
missense	3	1	295	14	1	314
nonsense	8					8
start loss		1	4			5
frameshift	12	4	5			21
inframe indel			12			12
splice donor/acceptor (+/-2bp)	2	4	2			8
splice region			7	20	1	28
non coding		1	35	85	35	156
Total	25	11	355	240	41

Highest pathogenic variant AF is 0.0000131

Variants in SQSTM1

This is a list of pathogenic ClinVar variants found in the SQSTM1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-179806526-G-A		not specified	Uncertain significance (Jun 22, 2021)
5-179820612-C-T			Likely benign (Sep 29, 2018)
5-179820717-AG-A			Likely benign (Aug 26, 2019)
5-179820718-G-A			Likely benign (Feb 21, 2019)
5-179820747-G-A			Benign (Feb 14, 2019)
5-179820766-T-C			Likely benign (Mar 17, 2019)
5-179820798-G-C			Likely benign (Sep 23, 2018)
5-179820902-G-C		Bone Paget disease	Likely benign (Jul 03, 2018)
5-179820910-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 3	Uncertain significance (Feb 19, 2018)
5-179820911-C-T		Paget disease of bone 3	Uncertain significance (Jan 13, 2018)
5-179820912-G-A		Paget disease of bone 3	Benign (Jan 13, 2018)
5-179820919-G-A		Paget disease of bone 3	Uncertain significance (Jan 12, 2018)
5-179820920-C-T		Paget disease of bone 3	Uncertain significance (Jan 12, 2018)
5-179820930-G-C		Paget disease of bone 3	Uncertain significance (Jan 12, 2018)
5-179820931-C-T		SQSTM1-related disorder	Likely benign (Dec 14, 2023)
5-179820932-T-G			Uncertain significance (Jul 01, 2024)
5-179820937-A-G		Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Paget disease of bone 2, early-onset • Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset	Conflicting classifications of pathogenicity (Aug 07, 2023)
5-179820938-T-A		Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset	Pathogenic (Oct 10, 2016)
5-179820939-G-A		Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Paget disease of bone 2, early-onset	Uncertain significance (May 10, 2021)
5-179820939-G-C		Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Paget disease of bone 2, early-onset	Uncertain significance (Feb 19, 2022)
5-179820941-C-T		Paget disease of bone 2, early-onset;Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 • Inborn genetic diseases	Uncertain significance (Dec 11, 2023)
5-179820944-C-T		Paget disease of bone 2, early-onset;Frontotemporal dementia and/or amyotrophic lateral sclerosis 1	Uncertain significance (Dec 13, 2022)
5-179820945-G-A		Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Paget disease of bone 2, early-onset	Likely benign (Nov 14, 2023)
5-179820950-C-A		See cases	Uncertain significance (Apr 04, 2020)
5-179820951-C-T		Frontotemporal dementia and/or amyotrophic lateral sclerosis 1;Paget disease of bone 2, early-onset	Likely benign (Apr 09, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SQSTM1	protein_coding	protein_coding	ENST00000389805	8	31691

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000860	0.986	125727	0	21	125748	0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.940	304	261	1.16	0.0000174	2843
Missense in Polyphen		72	65.532	1.0987		725
Synonymous	-2.24	138	108	1.27	0.00000783	872
Loss of Function	2.18	8	18.0	0.445	8.68e-7	215

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000618	0.0000615
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.00	0.00
European (Non-Finnish)	0.0000968	0.0000967
Middle Eastern	0.000326	0.000326
South Asian	0.0000980	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Autophagy receptor required for selective macroautophagy (aggrephagy). Functions as a bridge between polyubiquitinated cargo and autophagosomes. Interacts directly with both the cargo to become degraded and an autophagy modifier of the MAP1 LC3 family (PubMed:16286508, PubMed:20168092, PubMed:24128730, PubMed:28404643, PubMed:22622177). Along with WDFY3, involved in the formation and autophagic degradation of cytoplasmic ubiquitin- containing inclusions (p62 bodies, ALIS/aggresome-like induced structures). Along with WDFY3, required to recruit ubiquitinated proteins to PML bodies in the nucleus (PubMed:24128730, PubMed:20168092). May regulate the activation of NFKB1 by TNF- alpha, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. May regulate signaling cascades through ubiquitination. Adapter that mediates the interaction between TRAF6 and CYLD (By similarity). May be involved in cell differentiation, apoptosis, immune response and regulation of K(+) channels. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle- associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport (PubMed:27368102). {ECO:0000250|UniProtKB:O08623, ECO:0000250|UniProtKB:Q64337, ECO:0000269|PubMed:10356400, ECO:0000269|PubMed:10747026, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:12471037, ECO:0000269|PubMed:15340068, ECO:0000269|PubMed:15802564, ECO:0000269|PubMed:15911346, ECO:0000269|PubMed:15953362, ECO:0000269|PubMed:16079148, ECO:0000269|PubMed:16286508, ECO:0000269|PubMed:19931284, ECO:0000269|PubMed:20168092, ECO:0000269|PubMed:22622177, ECO:0000269|PubMed:24128730, ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:28404643}.
• Disease: DISEASE: Paget disease of bone 3 (PDB3) [MIM:167250]: A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. {ECO:0000269|PubMed:11992264, ECO:0000269|PubMed:12374763, ECO:0000269|PubMed:14584883, ECO:0000269|PubMed:15125799, ECO:0000269|PubMed:15146436, ECO:0000269|PubMed:15176995, ECO:0000269|PubMed:15207768, ECO:0000269|PubMed:19931284}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinated protein aggregates. {ECO:0000269|PubMed:16286508}.; DISEASE: Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (FTDALS3) [MIM:616437]: A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Some FTDALS3 patients may also develop Paget disease of bone. {ECO:0000269|PubMed:22084127, ECO:0000269|PubMed:24042580, ECO:0000269|PubMed:24899140, ECO:0000269|PubMed:25114083}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (NADGP) [MIM:617145]: A neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. Disease onset is in childhood or adolescence. NADGP transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:27545679}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158]: An autosomal dominant myopathy with adult onset, characterized by muscle weakness of the distal upper and lower limbs, walking difficulties, and proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles. {ECO:0000269|PubMed:26208961}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mitophagy - animal - Homo sapiens (human);Necroptosis - Homo sapiens (human);Fluid shear stress and atherosclerosis - Homo sapiens (human);Osteoclast differentiation - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;IL-1 signaling pathway;RANKL-RANK (Receptor activator of NFKB (ligand)) Signaling Pathway;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Apoptosis-related network due to altered Notch3 in ovarian cancer;Nuclear Receptors Meta-Pathway;NRF2 pathway;Interleukin-1 Induced Activation of NF-kappa-B;Pathways in clear cell renal cell carcinoma;Senescence and Autophagy in Cancer;Signal Transduction;Signaling by Interleukins;p75NTR signals via NF-kB;Cytokine Signaling in Immune system;Interleukin-1 signaling;Immune System;Pink/Parkin Mediated Mitophagy;Mitophagy;IL1;NRIF signals cell death from the nucleus;p75NTR recruits signalling complexes;NF-kB is activated and signals survival;Death Receptor Signalling;p75 NTR receptor-mediated signalling;RANKL;Neurotrophic factor-mediated Trk receptor signaling;TNF receptor signaling pathway ;p75(NTR)-mediated signaling;Cell death signalling via NRAGE, NRIF and NADE;IL1-mediated signaling events;Interleukin-1 family signaling (Consensus)

Recessive Scores

• pRec: 0.237

Intolerance Scores

• loftool: 0.0328
• rvis_EVS: -0.26
• rvis_percentile_EVS: 34.88

Haploinsufficiency Scores

• pHI: 0.850
• hipred: Y
• hipred_score: 0.596
• ghis: 0.544

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.834

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Sqstm1
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; immune system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: sqstm1
• Affected structure: motor neuron
• Phenotype tag: abnormal
• Phenotype quality: decreased branchiness

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;autophagy of mitochondrion;mitophagy;positive regulation of protein phosphorylation;immune system process;response to ischemia;protein phosphorylation;ubiquitin-dependent protein catabolic process;autophagy;apoptotic process;mitochondrion organization;endosome organization;protein localization;regulation of mitochondrion organization;endosomal transport;macroautophagy;cell differentiation;intracellular signal transduction;aggrephagy;positive regulation of apoptotic process;negative regulation of apoptotic process;regulation of I-kappaB kinase/NF-kappaB signaling;negative regulation of growth of symbiont in host;positive regulation of transcription by RNA polymerase II;regulation of Ras protein signal transduction;protein heterooligomerization;regulation of protein complex stability;selective autophagy;interleukin-1-mediated signaling pathway;response to mitochondrial depolarisation;positive regulation of long-term synaptic potentiation;positive regulation of protein localization to plasma membrane;protein localization to perinuclear region of cytoplasm
• Cellular component: phagophore assembly site;P-body;nucleoplasm;cytoplasm;mitochondrion;late endosome;autophagosome;endoplasmic reticulum;cytosol;inclusion body;aggresome;PML body;sarcomere;intracellular membrane-bounded organelle;amphisome;autolysosome;extracellular exosome;sperm midpiece;Lewy body
• Molecular function: protein serine/threonine kinase activity;protein kinase C binding;protein binding;zinc ion binding;enzyme binding;protein kinase binding;receptor tyrosine kinase binding;ubiquitin protein ligase binding;ionotropic glutamate receptor binding;SH2 domain binding;identical protein binding;protein homodimerization activity;ubiquitin binding;K63-linked polyubiquitin modification-dependent protein binding