The SLC11A2 c.1197G>C (p.Glu399Asp) variant is a missense variant that occurs in a splice region. It was identified in a single homozygous individual with hypochromic microcytic anemia with iron overload (Mims et al. 2005; Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005; Gunshin et al. 2005). The unaffected parents and sibling of the affected individual were confirmed carriers of the variant. The p.Glu399Asp variant was absent from 108 healthy controls and is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. In addition to resulting in a full-length transcript containing a p.Glu399Asp amino acid substitution, this variant, which is also described as c.1285G>C, also disrupts normal splicing of pre-mRNA, leading to skipping of exon 12. Various methods of functional testing indicated that the full-length protein with the p.Glu399Asp variant behaved comparably to the wild type protein, whereas the protein lacking exon 12 was non-functional (Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005). Based on the available evidence, the p.Glu399Asp variant is classified as a variant of uncertain significance but suspicious for pathogenicity for hypochromic microcytic anemia with iron overload. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_000617.3(SLC11A2):c.1197G>C (p.Glu399Asp)
Germline
Classification
Help
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.
(2)
Help
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.
Uncertain significance
2
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000617.3(SLC11A2):c.1197G>C (p.Glu399Asp)
Variation ID: 9074 Accession: VCV000009074.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.12 12: 50992810 (GRCh38) [ NCBI UCSC ] 12: 51386593 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 May 27, 2019 Sep 17, 2018 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000617.3:c.1197G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000608.1:p.Glu399Asp missense NM_001174125.2:c.1284G>C NP_001167596.1:p.Glu428Asp missense NM_001174126.2:c.1197G>C NP_001167597.1:p.Glu399Asp missense NM_001174127.2:c.1197G>C NP_001167598.1:p.Glu399Asp missense NM_001174128.2:c.1197G>C NP_001167599.1:p.Glu399Asp missense NM_001174129.2:c.1197G>C NP_001167600.1:p.Glu399Asp missense NM_001174130.2:c.1185G>C NP_001167601.1:p.Glu395Asp missense NM_001379446.1:c.1284G>C NP_001366375.1:p.Glu428Asp missense NM_001379447.2:c.1197G>C NP_001366376.1:p.Glu399Asp missense NM_001379448.1:c.1185G>C NP_001366377.1:p.Glu395Asp missense NM_001379455.1:c.1284G>C NP_001366384.1:p.Glu428Asp missense NM_001414744.1:c.1197G>C NP_001401673.1:p.Glu399Asp missense NM_001414745.1:c.1197G>C NP_001401674.1:p.Glu399Asp missense NM_001414746.1:c.1197G>C NP_001401675.1:p.Glu399Asp missense NM_001414747.1:c.1086G>C NP_001401676.1:p.Glu362Asp missense NM_001414748.1:c.1086G>C NP_001401677.1:p.Glu362Asp missense NM_001414749.1:c.960G>C NP_001401678.1:p.Glu320Asp missense NM_001414750.1:c.960G>C NP_001401679.1:p.Glu320Asp missense NR_033421.2:n.1230G>C non-coding transcript variant NR_033422.2:n.1305G>C non-coding transcript variant NR_166668.1:n.1310G>C non-coding transcript variant NR_166669.1:n.1305G>C non-coding transcript variant NR_166670.1:n.1310G>C non-coding transcript variant NR_183175.1:n.1546G>C NR_183176.1:n.1383G>C NR_183177.1:n.1546G>C NR_183178.1:n.1551G>C NR_183179.1:n.1551G>C NC_000012.12:g.50992810C>G NC_000012.11:g.51386593C>G NG_021139.1:g.40466G>C LRG_1160:g.40466G>C LRG_1160t1:c.1197G>C LRG_1160p1:p.Glu399Asp LRG_1160t2:c.1284G>C LRG_1160p2:p.Glu428Asp LRG_1160t3:c.1185G>C LRG_1160p3:p.Glu395Asp LRG_1160t4:c.1197G>C LRG_1160p4:p.Glu399Asp - Protein change
- E399D, E428D, E395D, E320D, E362D
- Other names
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- Canonical SPDI
- NC_000012.12:50992809:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SLC11A2 | - | - |
GRCh38 GRCh37 |
136 | 153 | |
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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, single submitter
|
Sep 17, 2018 | RCV000009642.6 |
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. |
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|---|---|---|---|---|---|
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Uncertain significance
(Sep 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Microcytic anemia with liver iron overload
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914584.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC11A2 c.1197G>C (p.Glu399Asp) variant is a missense variant that occurs in a splice region. It was identified in a single homozygous individual with hypochromic … (more)
The SLC11A2 c.1197G>C (p.Glu399Asp) variant is a missense variant that occurs in a splice region. It was identified in a single homozygous individual with hypochromic microcytic anemia with iron overload (Mims et al. 2005; Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005; Gunshin et al. 2005). The unaffected parents and sibling of the affected individual were confirmed carriers of the variant. The p.Glu399Asp variant was absent from 108 healthy controls and is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. In addition to resulting in a full-length transcript containing a p.Glu399Asp amino acid substitution, this variant, which is also described as c.1285G>C, also disrupts normal splicing of pre-mRNA, leading to skipping of exon 12. Various methods of functional testing indicated that the full-length protein with the p.Glu399Asp variant behaved comparably to the wild type protein, whereas the protein lacking exon 12 was non-functional (Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005). Based on the available evidence, the p.Glu399Asp variant is classified as a variant of uncertain significance but suspicious for pathogenicity for hypochromic microcytic anemia with iron overload. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Feb 01, 2005)
|
no assertion criteria provided
Method: literature only
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ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029860.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with hypochromic microcytic anemia and iron overload (206100), Mims et al. (2005) found homozygosity for a 1285G-C transversion in exon 12 of … (more)
In a patient with hypochromic microcytic anemia and iron overload (206100), Mims et al. (2005) found homozygosity for a 1285G-C transversion in exon 12 of the DMT1 gene, resulting in a glu399-to-asp substitution (E399D). The predominant effect of the substitution was preferential skipping of exon 12 during processing of pre-mRNA. The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutations, the mk mouse and the Belgrade rat, the patient was iron overloaded. (less)
|
Comment:
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:
The SLC11A2 c.1197G>C (p.Glu399Asp) variant is a missense variant that occurs in a splice region. It was identified in a single homozygous individual with hypochromic microcytic anemia with iron overload (Mims et al. 2005; Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005; Gunshin et al. 2005). The unaffected parents and sibling of the affected individual were confirmed carriers of the variant. The p.Glu399Asp variant was absent from 108 healthy controls and is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. In addition to resulting in a full-length transcript containing a p.Glu399Asp amino acid substitution, this variant, which is also described as c.1285G>C, also disrupts normal splicing of pre-mRNA, leading to skipping of exon 12. Various methods of functional testing indicated that the full-length protein with the p.Glu399Asp variant behaved comparably to the wild type protein, whereas the protein lacking exon 12 was non-functional (Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005). Based on the available evidence, the p.Glu399Asp variant is classified as a variant of uncertain significance but suspicious for pathogenicity for hypochromic microcytic anemia with iron overload. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of the E399D mutation in SLC11A2. | Gunshin H | Blood | 2005 | PMID: 16140868 |
| Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake. | Priwitzerova M | Blood | 2005 | PMID: 16091455 |
| Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload. | Lam-Yuk-Tseung S | Blood cells, molecules & diseases | 2005 | PMID: 16023393 |
| Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. | Mims MP | Blood | 2005 | PMID: 15459009 |
Text-mined citations for rs121918365 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 09, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.