Mendeliome
Gene: PSMB10 Green List (high evidence)ClinGen classification: Limited
Severe combined immunodeficiency, MONDO:0015974, PSMB10-related
Heterozygous germline variants in PSMB10 were first reported in relationship to PSMB10-related severe combined immunodeficiency in 2022 (PMID: 36250618). Reports describe patients that present early in life with T-/B-/natural killer (NK) cell+ severe combined immunodeficiency with some patients also developing Omenn syndrome (PMID:38503300). All cases are reported to arise from heterozygous, likely de novo missense mutations (two mutations across seven cases) that are predicted to result in a dominant-negative impact on the function of the PSMB10 encoded protein, β2i. β2i is a component of the immunoproteasome and thymoproteasome, which are unique proteasomes with altered formation kinetics and antigen processing capabilities compared to the standard proteasome. These missense mutations are hypothesized to alter steric interactions with other components of the proteasome, destabilizing proteasome formation and structure. Studies have shown that these PSMB10 variants likely have an intrinsic impact on the function and survival of thymic epithelial cells (TEC), thymocytes and peripheral lymphocytes (PMID:29654304, 39734035). Of note, bone marrow transplant has not been curative for most patients, supporting the findings that PSMB10 variants impact both the hematopoietic and thymic components of the immune system. A mouse model harboring a heterozygous missense mutation in Psmb10 partially phenocopies the human disease, exhibiting T and B cell lymphopenia and poor antigen-specific T cell function (PMID:29654304). In summary, there is currently limited evidence to support this gene-disease relationship.
This classification was approved by the ClinGen SCID-CID Working Group on 4/17/2025 (SOP VersioCreated: 14 Aug 2025, 11:13 p.m. | Last Modified: 14 Aug 2025, 11:13 p.m.
Panel Version: 1.2832
Green List (high evidence)
PMID 38503300: Six individuals with three de novo missense variants. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash.Created: 2 Apr 2024, 7:24 a.m. | Last Modified: 2 Apr 2024, 7:24 a.m.
Panel Version: 1.1626
PMID 37600812: 3 additional unrelated patients with compound heterozygous variants with structural modelling of proteasome assembly.Created: 6 Nov 2023, 8:07 a.m. | Last Modified: 6 Nov 2023, 8:07 a.m.
Panel Version: 1.1358
PSMB10 is part of the immunoproteasome, and other components cause auto inflammatory disorders. Single individual with homozygous missense variant reported.
Sources: LiteratureCreated: 30 Apr 2020, 7:46 a.m.
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Proteasome-associated autoinflammatory syndrome 5, MIM# 619175; Severe combined immunodeficiency, MONDO:0015974, PSMB10-related
Publications
Phenotypes for gene: PSMB10 were changed from Proteasome-associated autoinflammatory syndrome 5, MIM# 619175 to Proteasome-associated autoinflammatory syndrome 5, MIM# 619175; Severe combined immunodeficiency, MONDO:0015974, PSMB10-related
Publications for gene: PSMB10 were set to 31783057; 37600812
Mode of inheritance for gene: PSMB10 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PSMB10 were set to 31783057
Gene: psmb10 has been classified as Green List (High Evidence).
Phenotypes for gene: PSMB10 were changed from Autoinflammatory syndrome to Proteasome-associated autoinflammatory syndrome 5, MIM# 619175
Gene: psmb10 has been classified as Red List (Low Evidence).
gene: PSMB10 was added gene: PSMB10 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: PSMB10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSMB10 were set to 31783057 Phenotypes for gene: PSMB10 were set to Autoinflammatory syndrome Review for gene: PSMB10 was set to RED
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.