1. Panels
  2. Fetal anomalies
  3. VPS50
Genes in panel
Prev Next
STRs in panel
Prev Next
Regions in panel
Prev Next

Fetal anomalies

Gene: VPS50

Amber List (moderate evidence)
VPS50 (VPS50, EARP/GARPII complex subunit)
EnsemblGeneIds (GRCh38): ENSG00000004766
EnsemblGeneIds (GRCh37): ENSG00000004766
OMIM: 616465, Gene2Phenotype
VPS50 is in 6 panels

2 reviews

Ain Roesley (Victorian Clinical Genetics Services)

I don't know

1x proband Chet for a nonsense p.(Lys5*) and a complex structural variant of a 4.3Mb inversion, flanked by 170kb and 428kb deletions, respectively. The 428kb deletion spans the entire VPS50 gene.

Sanger confirmed the Lys5* to be 'homozygous' in the proband.

Phenotypes include:
severe ID, muscular hypotonia, sensorineural hearing impairment, microcephaly, nystagmus, seizures, hypoplastic corpus callous, neonatal low GGT cholesatsis, hepatomegaly, failure to thrive

AMBER on this panel as this 3rd proband had post-natal microcephaly
Created: 3 Jul 2024, 3:05 a.m. | Last Modified: 3 Jul 2024, 3:05 a.m.
Panel Version: 1.252

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

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

Created: 3 Jul 2024, 3:05 a.m.
Last Modified: 3 Jul 2024, 3:05 a.m.
Panel version: 1.252

Chirag Patel (Genetic Health Queensland)

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.
Sources: Expert list
Created: 28 Feb 2022, 6:47 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685

Publications

Created: 28 Feb 2022, 6:47 a.m.

Panel version: 0.4305

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Expert list
Phenotypes
  • Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685
OMIM
616465
Clinvar variants
Variants in VPS50
Penetrance
None
Publications
Panels with this gene

History Filter Activity

3 Jul 2024, Gel status: 2

Set publications

Ain Roesley (Victorian Clinical Genetics Services)

Publications for gene: VPS50 were set to PMID: 34037727

28 Feb 2022, Gel status: 2

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

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

28 Feb 2022, Gel status: 2

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

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

28 Feb 2022, Gel status: 1

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

Chirag Patel (Genetic Health Queensland)

gene: VPS50 was added gene: VPS50 was added to Fetal anomalies. Sources: Expert list Mode of inheritance for gene: VPS50 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: VPS50 were set to PMID: 34037727 Phenotypes for gene: VPS50 were set to Neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis , MIM#619685 Review for gene: VPS50 was set to AMBER