NM_000032.5(ALAS2):c.-15-2188A>G AND X-linked sideroblastic anemia 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 2, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003226058.3

Allele description [Variation Report for NM_000032.5(ALAS2):c.-15-2188A>G]

NM_000032.5(ALAS2):c.-15-2188A>G

Genes:

ALAS2:5'-aminolevulinate synthase 2 [Gene - OMIM - HGNC]
LOC108663984:ALAS2 intron 1 and 3 erythroid regulatory elements [Gene]
PAGE2B:PAGE family member 2B [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.21

Genomic location:

Preferred name:

NM_000032.5(ALAS2):c.-15-2188A>G

Other names:

NM_001037968.4:c.-50-346A>G

HGVS:

NC_000023.11:g.55028203T>C
NG_008983.1:g.7862A>G
NG_051542.1:g.4547T>C
NM_000032.5:c.-15-2188A>GMANE SELECT
NM_001037967.4:c.-15-2188A>G
NM_001037968.4:c.-50-346A>G
LRG_1163t1:c.-15-2188A>G
LRG_1163:g.7862A>G
NC_000023.10:g.55054636T>C

Molecular consequence:

NM_000032.5:c.-15-2188A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001037967.4:c.-15-2188A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001037968.4:c.-50-346A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: X-linked sideroblastic anemia 1
Synonyms:: Erythroid 5-aminolevulinate synthase deficiency; X chromosome-linked sideroblastic anemia; ANEMIA, SIDEROBLASTIC, 1, PYRIDOXINE REFRACTORY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0020721; MedGen: C4551511; Orphanet: 75563; OMIM: 300751

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Pectobacterium carotovorum strain BP9250 DnaJ gene, partial cds
Pectobacterium carotovorum strain BP9250 DnaJ gene, partial cds
gi|2642044888|gb|OR521305.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003922152	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 2, 2023)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 24166784, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003922152

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 2, 2023)

germline

curation

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations.

Campagna DR, de Bie CI, Schmitz-Abe K, Sweeney M, Sendamarai AK, Schmidt PJ, Heeney MM, Yntema HG, Kannengiesser C, Grandchamp B, Niemeyer CM, Knoers NV, Swart S, Marron G, van Wijk R, Raymakers RA, May A, Markianos K, Bottomley SS, Swinkels DW, Fleming MD.

Am J Hematol. 2014 Mar;89(3):315-9. doi: 10.1002/ajh.23616. Epub 2013 Nov 20. Erratum in: Am J Hematol. 2014 Jun;89(6):670.

PubMed [citation]

PMID:: 24166784
PMCID:: PMC3943703

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003922152.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The hemizygous c.-15-2188A>G variant in ALAS2 was identified by our study in one individual with sideroblastic anemia. The c.-15-2188A>G variant in ALAS2 has been reported in six individuals with X-linked sideroblastic anemia (PMID: 31642437, PMID: 24166784). This variant was absent from large population studies. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. The c.-15-2188A>G variant is located in a region of ALAS2 that is essential for gene expression and multiple variants in this region have been reported in association with disease in the literature, suggesting that this variant is in a key functional domain and slightly supports pathogenicity (PMID: 23935018, PMID: 24166784). In vitro functional studies provide some evidence that the c.-15-2188A>G variant variant may slightly impact protein function (PMID: 24166784). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked sideroblastic anemia. ACMG/AMP Criteria applied: PS3_Supporting, PS4, PM1_Supporting, PM2_Supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 30, 2024

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