VCV002500873.1 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 2500873 Accession: VCV002500873.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.21 X: 55028203 (GRCh38) [ NCBI UCSC ] X: 55054636 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 7, 2023	May 6, 2023	May 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000032.5:c.-15-2188A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001037967.4:c.-15-2188A>G		intron variant
NM_001037968.4:c.-50-346A>G		intron variant
NC_000023.11:g.55028203T>C
NC_000023.10:g.55054636T>C
NG_008983.1:g.7862A>G
NG_051542.1:g.4547T>C
LRG_1163:g.7862A>G
LRG_1163t1:c.-15-2188A>G

... more HGVS ... less HGVS

Protein change

Other names

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

Canonical SPDI

NC_000023.11:55028202:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ALAS2		-	-	GRCh38 GRCh37	198	406
LOC108663984	-	-	-	GRCh38	-	134
PAGE2B	-	-	-	GRCh38 GRCh37	7	151

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
X-linked sideroblastic anemia 1	Likely pathogenic (1)	criteria provided, single submitter	May 2, 2023	RCV003226058.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (May 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	X-linked sideroblastic anemia 1 (X-linked inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003922152.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Publications: PubMed (1) PubMed: 24166784 Comment: 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 … (more) 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). (less)

Comment:

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).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
X-linked sideroblastic anemia due to ALAS2 intron 1 enhancer element GATA-binding site mutations.	Campagna DR	American journal of hematology	2014	PMID: 24166784

Text-mined citations for this variant ...

Record last updated Mar 30, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...