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Intellectual disability

Gene: TMEM63B

Green List (high evidence)
TMEM63B (transmembrane protein 63B)
EnsemblGeneIds (GRCh38): ENSG00000137216
EnsemblGeneIds (GRCh37): ENSG00000137216
TMEM63B is in 4 panels

4 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on mode of inheritance: There are sufficient biallelic cases with loss of function variants and phenotype that includes moderate-severe developmental delay as well as lung disease to change the mode of inheritance to BOTH monoallelic and biallelic, autosomal or pseudoautosomal subject to GMS review.
Created: 25 Jun 2026, 5:09 p.m. | Last Modified: 25 Jun 2026, 5:09 p.m.
Panel Version: 10.37
Heterozygous variants in TMEM63B are associated with Developmental and epileptic encephalopathy 118 (OMIM:621250, accessed 25th Jun 2026) with a gain-of-function mechanism proposed.

PMID: 42259295 Chan et al 2026 report five individuals from four unrelated families with childhood interstitial lung disease and biallelic predicted loss-of-function variants in TMEM63B. Other phenotypic characteristics include moderate/severe developmental delay (5/5), white matter changes, (1/5), mild global atrophy on brain imaging (1/5) and severe short stature (2/5). None of the individuals had epilepsy or hearing loss.

Individuals were from Saudi Arabian, Malay, European and Native American ethnicities. 5 different variants were reported including nonsense, frameshift and splice donor variants. In family A a heterozygous ABCA3 missense variant of unknown significance was also inherited from the mother. Biallelic variants in ABCA3 are associated with Surfactant metabolism dysfunction, pulmonary, 3, OMIM:610921.

The authors report that while there are 53 TMEM63B pLoF variants in gnomAD v.4.1.0 database none are in the homozygous state. Histopathological examination of lung tissue also showed a pattern consistent with surfactant dysfunction.

The authors conclude that biallelic loss of function variants result in a distinct pulmonary-predominant phenotype characterized by hypoxemia, early-onset respiratory failure, histological features of surfactant dysfunction, and chest imaging consistent with chILD. Moderate to severe developmental delay was reported in all individuals.
Created: 25 Jun 2026, 5:05 p.m. | Last Modified: 25 Jun 2026, 5:07 p.m.
Panel Version: 10.36

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275

Publications

Created: 25 Jun 2026, 5:05 p.m.
Last Modified: 25 Jun 2026, 5:07 p.m.
Panel version: 10.36

Arina Puzriakova (Genomics England Curator)

Comment on phenotypes: OMIM phenotype accessed on 20-03-2026
Created: 20 Mar 2026, 11:27 a.m. | Last Modified: 20 Mar 2026, 11:27 a.m.
Panel Version: 9.334
Created: 20 Mar 2026, 11:27 a.m.
Last Modified: 20 Mar 2026, 11:27 a.m.
Panel version: 9.334

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: There is sufficient evidence available (17 unrelated cases) in support of promoting this gene to green rating in the next GMS review.
Created: 28 Jul 2023, 6:34 p.m. | Last Modified: 28 Jul 2023, 6:34 p.m.
Panel Version: 5.221
PMID:37421948 - 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment were identified with ten distinct heterozygous variants inTMEM63B. The variants occurred de novo in 16/17 individuals for whom parental DNA was available and either missense or in-frame. All individuals had global developmental delay, with moderate-to-profound intellectual disability and severe motor impairment.
Sources: Literature
Created: 28 Jul 2023, 6:32 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100062

Publications

Created: 28 Jul 2023, 6:32 p.m.

Panel version: 5.220

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • NHS GMS
  • Expert Review Green
  • Literature
Phenotypes
  • Developmental and epileptic encephalopathy 118, OMIM:621250
  • developmental and epileptic encephalopathy, MONDO:0100062
  • autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder
  • lung disorder, MONDO:0005275
Tags
Q2_26_MOI
Clinvar variants
Variants in TMEM63B
Penetrance
None
Publications
Panels with this gene

History Filter Activity

25 Jun 2026, Gel status: 3

Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder; lung disorder, MONDO:0005275

25 Jun 2026, Gel status: 3

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: TMEM63B were changed from Developmental and epileptic encephalopathy 118, OMIM:621250 to Developmental and epileptic encephalopathy 118, OMIM:621250; developmental and epileptic encephalopathy, MONDO:0100062; autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder,; lung disorder, MONDO:0005275

25 Jun 2026, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: TMEM63B were set to 37421948; 42259295

25 Jun 2026, Gel status: 3

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: TMEM63B were set to 37421948

25 Jun 2026, Gel status: 3

Set mode of inheritance

Eleanor Williams (Genomics England Curator)

Mode of inheritance for gene: TMEM63B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

25 Jun 2026, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q2_26_MOI tag was added to gene: TMEM63B.

20 Mar 2026, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TMEM63B were changed from developmental and epileptic encephalopathy, MONDO:0100062 to Developmental and epileptic encephalopathy 118, OMIM:621250

20 Mar 2026, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag gene-checked was removed from gene: TMEM63B.

9 May 2024, Gel status: 3

Added Tag

Eleanor Williams (Genomics England Curator)

Tag gene-checked tag was added to gene: TMEM63B.

3 May 2024, Gel status: 3

Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_23_promote_green was removed from gene: TMEM63B.

3 May 2024, Gel status: 3

Added New Source, Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source Expert Review Green was added to TMEM63B. Source NHS GMS was added to TMEM63B. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

28 Jul 2023, Gel status: 2

Entity classified by Genomics England curator

Achchuthan Shanmugasundram (Genomics England Curator)

Gene: tmem63b has been classified as Amber List (Moderate Evidence).

28 Jul 2023, Gel status: 1

Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q3_23_promote_green tag was added to gene: TMEM63B.

28 Jul 2023, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Achchuthan Shanmugasundram (Genomics England Curator)

gene: TMEM63B was added gene: TMEM63B was added to Intellectual disability - microarray and sequencing. Sources: Literature Mode of inheritance for gene: TMEM63B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM63B were set to 37421948 Phenotypes for gene: TMEM63B were set to developmental and epileptic encephalopathy, MONDO:0100062 Review for gene: TMEM63B was set to GREEN