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Cytopenias and congenital anaemias

Gene: VPS45

Green List (high evidence)

VPS45 (vacuolar protein sorting 45 homolog)
EnsemblGeneIds (GRCh38): ENSG00000136631
EnsemblGeneIds (GRCh37): ENSG00000136631
OMIM: 610035, Gene2Phenotype
VPS45 is in 3 panels

2 reviews

Louise Daugherty (Genomics England Curator)

Comment on list classification: Changed status from Red to Green based on literature.
Created: 22 Feb 2017, 10:30 a.m.
Comment on publications: (2 cases PMID:23738510,1 case PMID:23599270).
Both publications include consanguineous Palestinian families and although the publications do not refer to each other (the publications came out within the same month) there is no evidence to indicate they are related or not. However, there are still 3 unrelated families as PMID:23599270 asserts there is not a relationship between the 2 Palestinian families, who both had the Glu238Lys variant, and PMID:23738510, in addition to the Palestinian families (that may or may not be related to those in PMID:23599270) had one Moroccan family with a different causative variant Glu238Lys.
From PMID:23738510 : 5 affected children from 4 consanguineous Palestinian families with severe congenital neutropenia-5 had a homozygous missense mutation idenitified in the VPS45 gene Thr224Asn (c.671C→A; p.Thr224Asn).
Also, 2 affected children from 1 consanguineous Moroccan family who also had severe congenital neutropenia-5 had a homozygous missense mutation identified in the VPS45 gene but in Glu238Lys (c.712G→A; p.Glu238Lys).
Convincing functional evidence in PMID:23738510, VPS45 mutations were shown to cause this disease on the basis of the following findings: they fully segregated with the disease, were absent from 250 alleles of normal controls with the same genetic background and from published databases, caused structural alterations in VPS45, and were located in residues highly conserved among species. Furthermore, in both neutrophils and fibroblasts, the Thr224Asn mutation led to decreased VPS45 levels, affected proteins that interact with VPS45, impaired cell migration, and increased apoptosis. In addition, a zebrafish model with reduced vps45 protein had severe neutropenia, resembling that in the patients.
From PMID:23599270: 5 affected children from 2 unrelated consanguineous Palestinian families with severe congenital neutropenia-5 all had the same missense mutation idenitified in the VPS45 gene Thr224Asn (c.671C→A; p.Thr224Asn).
Created: 22 Feb 2017, 10:24 a.m.
Comment on mode of pathogenicity: Only missense variants have been reported in OMIM.
Created: 21 Feb 2017, 4:35 p.m.
Comment on phenotypes: added phenotypes/Synonyms from OMIM and Orphanet
Created: 21 Feb 2017, 3:42 p.m.
Comment on mode of inheritance: MOI from expert review and OMIM
Created: 21 Feb 2017, 3:38 p.m.

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Severe congenital neutropenia

Publications

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Neutropenia, severe congenital, 5, autosomal recessive, 615285
  • Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome
  • VPS45 deficiency
  • Severe congenital neutropenia
Tags
missense
OMIM
610035
Clinvar variants
Variants in VPS45
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

11 Mar 2017, Gel status: 4

panel promoted to version 1

Arianna Tucci (Genomics England Curator)

Promoted to V1 on 11 March 2017, after internal review and discussion with the clinical team.

24 Feb 2017, Gel status: 4

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

22 Feb 2017, Gel status: 4

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

21 Feb 2017, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for VPS45 were set to 23738510; 23599270

21 Feb 2017, Gel status: 1

Set publications

Louise Daugherty (Genomics England Curator)

Publications for VPS45 were set to 23738510;23599270

21 Feb 2017, Gel status: 1

Set mode of pathogenicity

Louise Daugherty (Genomics England Curator)

Mode of pathogenicity for VPS45 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

21 Feb 2017, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive, 615285; Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome; VPS45 deficiency; Severe congenital neutropenia

21 Feb 2017, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive, 615285; Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome; VPS45 deficiency; Severe congenital neutropenia

21 Feb 2017, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive,615285; Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome; VPS45 deficiency;Severe congenital neutropenia

21 Feb 2017, Gel status: 1

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for VPS45 were set to Neutropenia, severe congenital, 5, autosomal recessive,615285;Congenital neutropenia-bone marrow fibrosis-nephromegaly syndrome;VPS45 deficiency

21 Feb 2017, Gel status: 1

Set Mode of Inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for VPS45 was changed to BIALLELIC, autosomal or pseudoautosomal

17 Feb 2017, Gel status: 0

Created

Louise Daugherty (Genomics England Curator)

VPS45 was created by LouiseD

17 Feb 2017, Gel status: 1

Added New Source

Louise Daugherty (Genomics England Curator)

VPS45 was added to Cytopaenias and congenital anaemiaspanel. Sources: Radboud University Medical Center, Nijmegen