Non-acute porphyrias

Gene: ALAS2

Green List (high evidence)

ALAS2 (5'-aminolevulinate synthase 2)
EnsemblGeneIds (GRCh38): ENSG00000158578
EnsemblGeneIds (GRCh37): ENSG00000158578
OMIM: 301300, Gene2Phenotype
ALAS2 is in 16 panels

4 reviews

Ivone Leong (Genomics England Curator)

Green List (high evidence)

Comment when marking as ready: As discussed in the GMS Gastrohepatology Specialist Test Group webex call 14th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.
Created: 24 Jan 2019, 4:21 p.m.
Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: ALAS2; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given
Created: 7 Jan 2019, 3:53 p.m.

Sarah Leigh (Genomics England Curator)

Amber review assigned as this gene is Green on the V1 panel(s) named as a phenotype(s)
Created: 6 Jan 2017, 1:55 p.m.
Amber review assigned as this gene is Green on the V1 panel(s) named as a phenotype(s)
Created: 6 Jan 2017, 1:55 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
Erythropoietic protoporphyria, mild variant

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
  • Other
  • NHS GMS
Phenotypes
  • Protoporphyria, erythropoietic, X-linked OMIM:300752
  • X-linked erythropoietic protoporphyria MONDO:0010420
  • Anemia, sideroblastic, X-linked OMIM:300751
  • X-linked sideroblastic anemia 1 MONDO:0020721
OMIM
301300
Clinvar variants
Variants in ALAS2
Penetrance
None
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

17 Mar 2021, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: ALAS2 were changed from Protoporphyria, erythropoietic, X-linked, 300752; Anemia, sideroblastic, X-linked, 300751 to Protoporphyria, erythropoietic, X-linked OMIM:300752; X-linked erythropoietic protoporphyria MONDO:0010420; Anemia, sideroblastic, X-linked OMIM:300751; X-linked sideroblastic anemia 1 MONDO:0020721

24 Jan 2019, Gel status: 4

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: alas2 has been classified as Green List (High Evidence).

11 Jan 2019, Gel status: 4

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

Ivone Leong (Genomics England Curator)

Source Other was added to ALAS2. Mode of inheritance for gene ALAS2 was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Mode of pathogenicity for gene ALAS2 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added phenotypes Protoporphyria, erythropoietic, X-linked, 300752; Anemia, sideroblastic, X-linked, 300751 for gene: ALAS2 Publications for gene ALAS2 were changed from to 18760763; 23263862

7 Jan 2019, Gel status: 3

Added New Source, Status Update

Ivone Leong (Genomics England Curator)

Source Expert Review Green was added to ALAS2. Rating Changed from Red List (low evidence) to Green List (high evidence)

7 Jan 2019, Gel status: 1

Created, Added New Source, Set mode of inheritance

Ivone Leong (Genomics England Curator)

gene: ALAS2 was added gene: ALAS2 was added to Non-acute porphyrias. Sources: NHS GMS Mode of inheritance for gene: ALAS2 was set to