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Intellectual disability

Gene: VPS50

Amber List (moderate evidence)
VPS50 (VPS50, EARP/GARPII complex subunit)
EnsemblGeneIds (GRCh38): ENSG00000004766
EnsemblGeneIds (GRCh37): ENSG00000004766
OMIM: 616465, Gene2Phenotype
VPS50 is in 7 panels

3 reviews

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on phenotypes: Phenotype updated 22nd Apr 2026.
Created: 22 Apr 2026, 4:56 p.m. | Last Modified: 22 Apr 2026, 4:56 p.m.
Panel Version: 9.397
Comment on list classification: There are now 3 unrelated individuals reported with biallelic VPS50 variants and a concordant phenotype including cholestasis, ID / DD, CC hypoplasia on MRI, seizures, and failure to thrive. Hence, this gene can be promoted to Green at the next update.
Created: 22 Apr 2026, 4:54 p.m. | Last Modified: 22 Apr 2026, 4:54 p.m.
Panel Version: 9.395
3rd case:
PMID: 38876772 Hecher et al., 2024
18-month-old female patient, Vietnamese/German, with biallelic VPS50 variants: a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant, and a ~428 kb complex structural variation with VPS50 deletion chr7:g. (88798914_88969132del; 88969133_93232032inv; 93232033_93659940del), maternally inherited. The structural variant also affects the following genes: CALCR, GNGT1, HEPACAM2, ZNF804B - none of these are currently OMIM morbid for a mendelian disorder. Mother was unaffected.
Patient had severe ID / developmental delay, hypotonia, severe sensorineural hearing impairment, intermittent nystagmus, seizures (onset at 12 months), neonatal low GGT cholestasis, failure to thrive. Microcephaly was progressive (OFC at birth = 34.5 cm, Z score +0.29; OFC at 12 months = 42cm, Z score = -3.25). Brain MRI at 6mo and 17mo showed CC hypoplasia without other anomalies.
Interestingly, VPS50 mRNA in fibroblasts of the patient was similar to control levels, but VPS50 protein was absent - hinting at instability of the EARP complex.

VPS50 is associated with AR Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685 (OMIM accessed 22nd Apr 2026).
Created: 22 Apr 2026, 4:54 p.m. | Last Modified: 22 Apr 2026, 4:54 p.m.
Panel Version: 9.395

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216

Publications

Created: 22 Apr 2026, 4:54 p.m.
Last Modified: 22 Apr 2026, 4:54 p.m.
Panel version: 9.395

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 34037727. Both patients have severe microcephaly (-7.65 to -10.35 z-score), height at 2 years (-2.65 to -3.84 z-score), seizures, hypoplastic corpus callosum, neonatal cholestasis and feeding difficulties.

Based on the available evidence there is currently not enough evidence to support a gene-disease association. This gene has been given an Amber rating.
Created: 1 Oct 2021, 2:26 p.m. | Last Modified: 1 Oct 2021, 2:36 p.m.
Panel Version: 3.1322
Created: 1 Oct 2021, 2:26 p.m.
Last Modified: 1 Oct 2021, 2:36 p.m.
Panel version: 3.1322

Konstantinos Varvagiannis (Other)

I don't know

Schneeberger et al (2021 - PMID: 34037727) describe the phenotype of 2 unrelated individuals with biallelic VPS50 variants.

Common features included transient neonatal cholestasis, failure to thrive, severe DD with failure to achieve milestones (last examination at 2y and 2y2m respectively), postnatal microcephaly, seizures (onset at 6m and 25m) and irritability. There was corpus callosum hypoplasia on brain imaging.

Both individuals were homozygous for variants private to each family (no/not known consanguinity applying to each case). The first individual was homozygous for a splicing variant (NM_017667.4:c.1978-1G>T) and had a similarly unaffected sister deceased with no available DNA for testing. The other individual was homozygous for an in-frame deletion (c.1823_1825delCAA / p.(Thr608del)).

VPS50 encodes a critical component of the endosome-associated recycling protein (EARP) complex, which functions in recycling endocytic vesicles back to the plasma membrane [OMIM based on Schindler et al]. The complex contains VPS50, VPS51, VPS52, VPS53, the three latter also being components of GARP (Golgi-associated-retrograde protein) complex. GARP contains VPS54 instead of VPS50 and is required for trafficking of proteins to the trans-golgi network. Thus VPS50 (also named syndetin) and VPS54 function in the EARP and GARP complexes, to define directional movement of their endocytic vesicles [OMIM based on Schindler et al]. The VPS50 subunit is required for recycling of the transferrin receptor.

As discussed by Schneeberger et al (refs provided in text):
- VPS50 has a high expression in mouse and human brain as well as throughout mouse brain development.
- Mice deficient for Vps50 have not been reported. vps50 knockdown in zebrafish results in severe developmental defects of the body axis. Knockout mice for other proteins of the EARP/GARP complex (e.g. Vps52, 53 and 54) display embryonic lethality.

Studies performed by Schneeberger et al included:
- Transcript analysis for the 1st variant demonstrated skipping of ex21 (in patient derived fabriblasts) leading to an in frame deletion of 81 bp (r.1978_2058del) with predicted loss of 27 residues (p.Leu660_Leu686del).
- Similar VPS50 mRNA levels but significant reduction of protein levels (~5% and ~8% of controls) were observed in fibroblasts from patients 1 and 2. Additionally, significant reductions in the amounts of VPS52 and VPS53 protein levels were observed despite mRNA levels similar to controls. Overall, this suggested drastic reduction of functional EARP complex levels.
- Lysosomes appeared to have similar morphology, cellular distribution and likely unaffected function in patient fibroblasts.
- Transferrin receptor recycling was shown to be delayed in patient fibroblasts suggestive of compromise of endocytic-recycling function.

As the authors comment, the phenotype of both individuals with biallelic VPS50 variants overlaps with the corresponding phenotype reported in 15 subjects with biallelic VPS53 or VPS51 mutations notably, severe DD/ID, microcephaly and early onset epilepsy, CC anomalies. Overall, for this group, they propose the term "GARP and/or EARP deficiency disorders".

There is no VPS50-associated phenotype in OMIM or G2P. SysID includes VPS50 among the ID candidate genes.

Consider inclusion in other relevant gene panels (e.g. for neonatal cholestasis, epilepsy, microcephaly, growth failure in early infancy, corpus callosum anomalies, etc) with amber rating pending further reports.
Sources: Literature
Created: 13 Aug 2021, 1:35 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum

Publications

Created: 13 Aug 2021, 1:35 p.m.

Panel version: 3.1220

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685
  • neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216
Tags
Q2_26_promote_green
OMIM
616465
Clinvar variants
Variants in VPS50
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

22 Apr 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: VPS50 were changed from Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, OMIM:619685; neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, MONDO:0859216

22 Apr 2026, Gel status: 2

Set publications

Ida Ertmanska (Genomics England Curator)

Publications for gene: VPS50 were set to 34037727

22 Apr 2026, Gel status: 2

Removed Tag, Added Tag

Ida Ertmanska (Genomics England Curator)

Tag watchlist was removed from gene: VPS50. Tag Q2_26_promote_green tag was added to gene: VPS50.

1 Oct 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist tag was added to gene: VPS50.

1 Oct 2021, Gel status: 2

Removed Tag

Ivone Leong (Genomics England Curator)

Tag Q3_21_rating was removed from gene: VPS50.

1 Oct 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag Q3_21_rating tag was added to gene: VPS50.

1 Oct 2021, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: vps50 has been classified as Amber List (Moderate Evidence).

13 Aug 2021, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: VPS50 was added gene: VPS50 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to 34037727 Phenotypes for gene: VPS50 were set to Neonatal cholestatic liver disease; Failure to thrive; Profound global developmental delay; Postnatal microcephaly; Seizures; Abnormality of the corpus callosum Penetrance for gene: VPS50 were set to Complete Review for gene: VPS50 was set to AMBER