ClinVar Genomic variation as it relates to human health
NM_006563.5(KLF1):c.973G>A (p.Glu325Lys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006563.5(KLF1):c.973G>A (p.Glu325Lys)
Variation ID: 18447 Accession: VCV000018447.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12885001 (GRCh38) [ NCBI UCSC ] 19: 12995815 (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 Feb 13, 2014 Feb 14, 2024 Aug 10, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006563.5:c.973G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006554.1:p.Glu325Lys missense NC_000019.10:g.12885001C>T NC_000019.9:g.12995815C>T NG_013087.1:g.7203G>A NG_068129.1:g.91C>T LRG_825:g.7203G>A LRG_825t1:c.[973G>A] Q13351:p.Glu325Lys - Protein change
- E325K
- Other names
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- Canonical SPDI
- NC_000019.10:12885000:C:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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KLF1 | - | - |
GRCh38 GRCh37 |
47 | 171 | |
LOC117125591 | - | - | - | GRCh38 | - | 58 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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- | RCV000009567.8 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000990153.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 10, 2021 | RCV001507932.11 |
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
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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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Pathogenic
(Jun 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713782.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS2, PS4_moderate, PM1, PM2, PP3
Number of individuals with the variant: 1
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002151095.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid with lysine at codon 325 of the KLF1 protein (p.Glu325Lys). The glutamic acid residue is highly conserved and there … (more)
This sequence change replaces glutamic acid with lysine at codon 325 of the KLF1 protein (p.Glu325Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of congenital dyserythropoietic anemia (PMID: 21055716, 23522491, 28102861, 29200155, 29300242, 29396846). ClinVar contains an entry for this variant (Variation ID: 18447). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Experimental studies have shown that this missense change affects KLF1 function (PMID: 21055716, 21778342). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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BLOOD GROUP--LUTHERAN INHIBITOR
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140990.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Congenital dyserythropoietic anemia type 4
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073128.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.E325K in KLF1 (NM_006563.5) has been previously reported in dominant state with congenital dyseryhtropoietic anemia (Arnaud L et al). Functional studies reveal … (more)
The missense variant p.E325K in KLF1 (NM_006563.5) has been previously reported in dominant state with congenital dyseryhtropoietic anemia (Arnaud L et al). Functional studies reveal a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.E325K variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.E325K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glutamic acid residue at codon 325 of KLF1 is conserved in all mammalian species. The nucleotide c.973 in KLF1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Hemolytic anemia (present)
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Pathogenic
(Nov 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016382.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 01, 2013)
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no assertion criteria provided
Method: literature only
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ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IV
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029785.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2014 |
Comment on evidence:
In 2 unrelated patients with congenital dyserythropoietic anemia type IV (CDAN4; 613673), Arnaud et al. (2010) identified a heterozygous de novo 973G-A transition in exon … (more)
In 2 unrelated patients with congenital dyserythropoietic anemia type IV (CDAN4; 613673), Arnaud et al. (2010) identified a heterozygous de novo 973G-A transition in exon 3 of the KLF1 gene, resulting in a glu325-to-lys (E325K) substitution. One of the patients had previously been reported by Wickramasinghe et al. (1991). The phenotype was characterized by hydrops and severe anemia at birth, ineffective erythropoiesis, nucleated peripheral red blood cells, and absence of expression of CD44 (107269) and AQP1 (107776) on erythrocytes. Both patients also showed increased fetal hemoglobin. The E325K mutation occurred in a conserved residue in the second zinc finger domain, and structural modeling predicted that the mutation would stabilize the bond between KLF1 and DNA target sequences. Expression studies in human erythroid cells showed that the mutant E325K protein had similar expression and nuclear localization as the wildtype protein. However, the mutant protein showed markedly decreased transcriptional activity toward CD44 and AQP1 compared to wildtype, consistent with the clinical findings. The mutant KLF1 protein also showed a dominant-negative effect. The findings indicated that the KLF1 gene plays a critical role in the regulation of several genes during erythropoiesis, and that dysregulation of certain gene targets can result in dyserythropoiesis. By in vitro functional expression studies, Helias et al. (2013) demonstrated that the E325K mutant KLF1 protein retained transactivation activity for the BCAM (612773) promoter as well as, or ever better than, wildtype KLF1. The findings were consistent with the fact that CDAN4 is not associated with reduced levels of BCAM on red blood cells. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. | Russo R | American journal of hematology | 2018 | PMID: 29396846 |
KLF1 E325K-associated Congenital Dyserythropoietic Anemia Type IV: Insights Into the Variable Clinical Severity. | Ravindranath Y | Journal of pediatric hematology/oncology | 2018 | PMID: 29300242 |
A Case of Congenital Dyserythropoeitic Anemia Type IV Caused by E325K Mutation in Erythroid Transcription Factor KLF1. | Ortolano R | Journal of pediatric hematology/oncology | 2018 | PMID: 29200155 |
Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. | Muramatsu H | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28102861 |
Survey of variation in human transcription factors reveals prevalent DNA binding changes. | Barrera LA | Science (New York, N.Y.) | 2016 | PMID: 27013732 |
Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. | Jaffray JA | Blood cells, molecules & diseases | 2013 | PMID: 23522491 |
Molecular analysis of the rare in(Lu) blood type: toward decoding the phenotypic outcome of haploinsufficiency for the transcription factor KLF1. | Helias V | Human mutation | 2013 | PMID: 23125034 |
Mutations in the second zinc finger of human EKLF reduce promoter affinity but give rise to benign and disease phenotypes. | Singleton BK | Blood | 2011 | PMID: 21778342 |
A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. | Arnaud L | American journal of human genetics | 2010 | PMID: 21055716 |
Congenital dyserythropoietic anaemia with novel intra-erythroblastic and intra-erythrocytic inclusions. | Wickramasinghe SN | British journal of haematology | 1991 | PMID: 1659863 |
Text-mined citations for rs267607201 ...
HelpRecord last updated Apr 06, 2024
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.