Intellectual disability
Gene: PSMC3

PSMC3 (proteasome 26S subunit, ATPase 3)
EnsemblGeneIds (GRCh38): ENSG00000165916
EnsemblGeneIds (GRCh37): ENSG00000165916
OMIM: 186852, Gene2Phenotype
PSMC3 is in 8 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Created: 3 May 2024, 11:55 a.m. | Last Modified: 3 May 2024, 11:55 a.m.

Panel Version: 6.11

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Created: 3 May 2024, 11:55 a.m.
Last Modified: 3 May 2024, 11:55 a.m.
Panel version: 6.11

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: This gene can be promoted to green rating in the next GMS review.
Created: 9 Aug 2023, 11:01 a.m. | Last Modified: 14 Dec 2023, 11:18 a.m.

Panel Version: 5.347

Comment on mode of inheritance: There is sufficient evidence available for the association of monoallelic variants from this gene with intellectual disability. However, there is only one family reported with biallelic variants. Hence, the MOI is set as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Created: 9 Aug 2023, 11 a.m. | Last Modified: 14 Dec 2023, 11:17 a.m.

Panel Version: 5.347

PMID:32500975 - Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.

PMID:37256937 - 23 individuals with neurodevelopmental disorder were identified with 15 different de novo missense variants. Apart from one child (patient 2), all others had developmental delay characterised by speech delay (19/19) alone or with intellectual disability (16/18) and motor delay (15/19). In addition, structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune program.

The phenotype caused by recessive PSMC3 variants has been reported in OMIM (MIM #619354), but not in Gene2Phenotype. However, the phenotype caused by dominant variants has not yet been reported in either resources.
Created: 9 Aug 2023, 10:53 a.m. | Last Modified: 14 Dec 2023, 10:56 a.m.

Panel Version: 5.347

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354; neurodevelopmental disorder, MONDO:0700092

Publications

Created: 9 Aug 2023, 10:53 a.m.
Last Modified: 14 Dec 2023, 11:18 a.m.
Panel version: 5.239

Dmitrijs Rots (Children's Clinical University Hospital)

Green List (high evidence)

23 individuals with NDD due to 15 different de novo missense variants in PMID: 37256937.
Sources: Literature
Created: 24 Jun 2023, 6:42 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
neurodevelopmental delay

Publications

PMID: 37256937

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 24 Jun 2023, 6:42 a.m.

Panel version: 5.191

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

NHS GMS
Expert Review Green

Phenotypes

?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354
neurodevelopmental disorder, MONDO:0700092

OMIM

186852

Clinvar variants

Variants in PSMC3

Penetrance

None

Publications

Mode of Pathogenicity

Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Panels with this gene