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Intellectual disability

Gene: RNF13

Green List (high evidence)

RNF13 (ring finger protein 13)
EnsemblGeneIds (GRCh38): ENSG00000082996
EnsemblGeneIds (GRCh37): ENSG00000082996
OMIM: 609247, Gene2Phenotype
RNF13 is in 3 panels

4 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

Associated with relevant phenotype in OMIM and as probable Gen2Phen gene. At least 2 variants reported in 3 unrelated cases, together with supportive functional studies.

Gain-of-function mechanism has been reported, therefore the mutational spectrum may be limited and is still to be determined through further cases or further functional studies (view of Helen Britain, GeL Clincial Fellow).
Created: 23 Mar 2020, 5:12 p.m. | Last Modified: 30 Mar 2020, 1:21 p.m.
Panel Version: 3.23

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

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Three unrelated individuals with de novo missense variants in this gene, adjacent residues, one missense recurrent in two individuals, arguing for important functional role of this residue. Functional data presented supports GoF effect. Phenotype very consistent between affected individuals, including profound developmental delay.
Created: 10 Mar 2020, 5:28 a.m. | Last Modified: 10 Mar 2020, 5:28 a.m.
Panel Version: 3.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 73, MIM# 618379

Publications

Variants in this GENE are reported as part of current diagnostic practice

Catherine Snow (Genomics England)

Selected other as mode of pathogenicity as authors are predicting activating mechanism rather than LOF
Created: 24 Jun 2019, 2:32 p.m. | Last Modified: 24 Jun 2019, 2:32 p.m.
Panel Version: 0.192
Comment on list classification: RNF13 identified by expert review by Konstantinos Varvagiannis. Edvardson et al. (PMID: 30595371) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants. WES was performed on the individual and their parents. All individuals had severe ID and phenotype is supported that RNF13 is in OMIM and probable in Gene2Phenotype as Disease: Congenital Microcephaly Epileptic Encephalopathy Blindness and Failure to Thrive .
Two distinct variants were identified, variants are reported to not be LOF but hypothesised that gain of function mechanism. Therefore as mechanism unclear, only one case report in the supplementary material, limited phenotype evidence for the additional two affected individuals and that this is the first time of RNF13 being reported in literature, classifying RNF13 as Amber and awaiting advice from the clinical team.
Created: 28 May 2019, 4:28 p.m. | Last Modified: 1 Jul 2019, 10:50 a.m.
Panel Version: 0.196

Mode of pathogenicity
Other

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Edvardson et al. (doi.org/10.1016/j.ajhg.2018.11.018) report on 3 unrelated individuals with heterozygous de novo missense RNF13 variants.

Features included (rather borderline) congenital microcephaly, feeding difficulties, tone abnormalities, DD/ID (3/3), seizures (3/3), hearing loss and cortical visual impairment.

One individual harbored the p.Leu311Ser variant (NM_007282.4:c.932T>C) while 2 others the p.Leu312Pro (c.935T>C).

RNF13 encodes a protein known to interact and activate IRE1a, an endoplasmatic reticulum (ER) stress sensor.

The 2 variants are predicted in silico not to affect the tertiary structure of the protein. Further to this, RNF13 is tolerant to LoF variants (pLI of 0 in ExAC). Therefore a gain-of-function mechanism was hypothesized for the 2 missense variants and demonstrated for the Leu311Ser:
- Protein levels were similar to controls upon Western blotting in patient fibroblasts.
- Enhanced IRE1a activation was demonstrated in patient cells when compared to controls, confirming gain-of-function.
- Increased activation (/ER stress), in turn, resulted in abnormally increased apoptosis similarly to what is observed in other neurological disorders.

Fibroblast/lymphoblast cells were not available from individuals with the Leu312Pro variant although a similar mechanism is presumed.

Although neurodegeneration is suggested by the above pathophysiologic mechanism, this is manifested by failure to achieve milestones (rather than eg. regression after a normal period of postnatal development / loss of milestones).
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RNF13 is not associated with any phenotype in OMIM, nor in G2P.
This gene is not commonly included in gene panels for ID offered by diagnostic laboratories.
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As a result, RNF13 can be considered for inclusion in this panel possibly as green (or amber).
Sources: Literature
Created: 29 Dec 2018, 11:57 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Expert Review
  • Expert Review
Phenotypes
  • Cortical visual impairment
  • Epileptic encephalopathy, early infantile, 73, 618379
  • Failure to thrive
  • Seizures
  • Congenital microcephaly
  • Abnormal muscle tone
  • Feeding difficulties
  • Intellectual disability
  • Global developmental delay
  • Sensorineural hearing impairment
Tags
watchlist
OMIM
609247
Clinvar variants
Variants in RNF13
Penetrance
unknown
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

History Filter Activity

30 Mar 2020, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: rnf13 has been classified as Green List (High Evidence).

25 Jul 2019, Gel status: 2

Added Tag

Catherine Snow (Genomics England)

Tag watchlist tag was added to gene: RNF13.

25 Jul 2019, Gel status: 2

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review was added to RNF13. Source Expert Review Amber was added to RNF13. Added phenotypes Epileptic encephalopathy, early infantile, 73, 618379 for gene: RNF13 Publications for gene RNF13 were changed from to 30595371 Rating Changed from No List (delete) to Amber List (moderate evidence)

29 Dec 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: RNF13 was added gene: RNF13 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: RNF13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: RNF13 were set to Congenital microcephaly; Feeding difficulties; Failure to thrive; Abnormal muscle tone; Global developmental delay; Intellectual disability; Seizures; Cortical visual impairment; Sensorineural hearing impairment Penetrance for gene: RNF13 were set to unknown Mode of pathogenicity for gene: RNF13 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: RNF13 was set to GREEN