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Erythropoietic protoporphyria, mild variant

Gene: ALAS2

Green List (high evidence)

ALAS2 (5'-aminolevulinate synthase 2)
EnsemblGeneIds (GRCh38): ENSG00000158578
EnsemblGeneIds (GRCh37): ENSG00000158578
OMIM: 301300, Gene2Phenotype
ALAS2 is in 17 panels

2 reviews

Ellen McDonagh (Genomics England Curator)

Comment on list classification: Pathogenic variants reported in OMIM/ClinVar, and described as a recent discovery by the reviewer - two publications with multiple cases, with functional data supporting a gain-of-function mechanism.
Created: 29 Jan 2016, 3:40 p.m.
Comment on mode of pathogenicity: Gain of function - see Reviewer's comments and the publications.
Created: 29 Jan 2016, 3:31 p.m.
Described as "X-linked dominant" on expert list. Confirmed on OMIM.
Created: 29 Jan 2016, 3:23 p.m.
Transcript and phenotypes under "gene summary" were accidently copied over to the review on Nov 12th 2015 and were not provided by the reviewer.
Created: 12 Nov 2015, 1:43 p.m.

John McGrath (King's College London)

Green List (high evidence)

ALAS2 is a more recent discovery and a few cases of X-linked EPP have been reported _ mostly in males with females often asymptomatic or with minor scars in sun-exposed sites. Most mutations are small deletions or nonsense mutations near C-terminus which lead to increased enzyme activity (gain-of-function). Mutations in ALAS2 account for 2-5% of total cases in Europe (but up to 10% in North America). Mutations in ALAS2 may be under-recognised to date, but current data indicate that, taken together, mutations in FECH and ALAS2 account for ~94% of total EPP cases, i.e. further genetic heterogeneity is suspected in ~6% of cases.
Created: 12 Nov 2015, 1:34 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Anemia, sideroblastic, X-linked, 300751Protoporphyria, erythropoietic, X-linked, 300752

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
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • Expert list
Phenotypes
  • Anemia, sideroblastic, X-linked, 300751
  • Protoporphyria, erythropoietic, X-linked, 300752
OMIM
301300
Clinvar variants
Variants in ALAS2
Penetrance
Complete
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

29 Jan 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

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

29 Jan 2016, Gel status: 4

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for ALAS2 were set to Anemia, sideroblastic, X-linked, 300751; Protoporphyria, erythropoietic, X-linked, 300752

29 Jan 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

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

29 Jan 2016, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for ALAS2 were set to PMID: 18760763; 23263862

29 Jan 2016, Gel status: 1

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for ALAS2 were set to

29 Jan 2016, Gel status: 1

Set mode of pathogenicity

Ellen McDonagh (Genomics England Curator)

Mode of pathogenicity for ALAS2 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

8 May 2015, Gel status: 1

Upload gene information

Eik Haraldsdottir (Genomics England)

ALAS2 was added to Erythropoietic protoporphyria, mild variantpanel. Sources: Radboud University Medical Center, Nijmegen,Expert list

28 Apr 2015, Gel status: 1

Added New Source

GEL ()

ALAS2 was added to Erythropoietic protoporphyria, mild variantpanel. Sources: Radboud University Medical Center, Nijmegen