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NM_000032.5(ALAS2):c.895A>C (p.Lys299Gln) AND Sideroblastic anemia 1, late-onset

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 21, 2005
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000011218.5

Allele description [Variation Report for NM_000032.5(ALAS2):c.895A>C (p.Lys299Gln)]

NM_000032.5(ALAS2):c.895A>C (p.Lys299Gln)

Gene:
ALAS2:5'-aminolevulinate synthase 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Xp11.21
Genomic location:
Preferred name:
NM_000032.5(ALAS2):c.895A>C (p.Lys299Gln)
HGVS:
  • NC_000023.11:g.55017594T>G
  • NG_008983.1:g.18471A>C
  • NM_000032.5:c.895A>CMANE SELECT
  • NM_001037967.4:c.784A>C
  • NM_001037968.4:c.856A>C
  • NP_000023.2:p.Lys299Gln
  • NP_001033056.1:p.Lys262Gln
  • NP_001033057.1:p.Lys286Gln
  • LRG_1163t1:c.895A>C
  • LRG_1163:g.18471A>C
  • LRG_1163p1:p.Lys299Gln
  • NC_000023.10:g.55044027T>G
Protein change:
K262Q; LYS299GLN
Links:
OMIM: 301300.0005; dbSNP: rs137852303
NCBI 1000 Genomes Browser:
rs137852303
Molecular consequence:
  • NM_000032.5:c.895A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001037967.4:c.784A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001037968.4:c.856A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Sideroblastic anemia 1, late-onset
Synonyms:
Anemia, hereditary sideroblastic, late-onset
Identifiers:
MedGen: C4225593

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000031445OMIM
no assertion criteria provided
Pathogenic
(Sep 21, 2005)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.

Cotter PD, May A, Fitzsimons EJ, Houston T, Woodcock BE, al-Sabah AI, Wong L, Bishop DF.

J Clin Invest. 1995 Oct;96(4):2090-6.

PubMed [citation]
PMID:
7560104
PMCID:
PMC185849

Crystal structure of 5-aminolevulinate synthase, the first enzyme of heme biosynthesis, and its link to XLSA in humans.

Astner I, Schulze JO, van den Heuvel J, Jahn D, Schubert WD, Heinz DW.

EMBO J. 2005 Sep 21;24(18):3166-77. Epub 2005 Aug 25.

PubMed [citation]
PMID:
16121195
PMCID:
PMC1224682

Details of each submission

From OMIM, SCV000031445.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

Cotter et al. (1995) reported 2 unrelated cases of X-linked sideroblastic anemia-1 (SIDBA1; 300751) that were atypical in 2 respects: unlike the usual form which is manifest in the first 3 decades of life and in which the hematologic response to pyridoxine is variable and rarely complete, the 2 patients were highly pyridoxine-responsive and were in the geriatric age group. A previously unaffected 77-year-old male and an 81-year-old female, who were previously well, were found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A-to-C transversion in exon 7 (K299Q) of the ALAS2 gene in the man as well as his daughter, while the female proband showed a G-to-A transition in exon 5 (A172T; 301300.0006). The latter mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. The recombinant mutant ALAS2 enzyme of each patient had marked thermal lability. Addition of pyridoxal 5-prime-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of X-linked sideroblastic anemia could be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and, of course, ALAS2 mutations. Cotter et al. (1995) suggested that all patients with acquired sideroblastic anemia should be tested for pyridoxine responsiveness. Relatively modest deficiencies of folate or vitamin B12 may explain late-onset anemia in patients with previously compensated hemolytic states due to inherited cytoskeletal defects, e.g., hereditary spherocytosis, or glycolytic pathway enzyme deficiencies, e.g., pyruvate kinase deficiency. The authors stated that age-associated nutritional deficiencies due to subtle alterations in vitamin B6 availability or metabolism may unmask an inherited disorder when a mutation is present in a gene that encodes a protein highly dependent upon the normal availability of pyridoxal phosphate.

By crystal structure analysis of Alas2 from Rhodobacter capsulatus, Astner et al. (2005) determined that replacement of lys299 by glutamine causes decreased binding affinity of ALAS for sCoA. Patients with this mutation have been reported to respond to pyridoxine treatment; however, as PLP binding in ALAS is not affected by the mutation, the effect of pyridoxine supplementation may be indirect.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 23, 2022