VCV000056891.2 - ClinVar

NM_006563.5(KLF1):c.892G>C (p.Ala298Pro)

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.

(3)

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.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006563.5(KLF1):c.892G>C (p.Ala298Pro)

Variation ID: 56891 Accession: VCV000056891.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 12885338 (GRCh38) [ NCBI UCSC ] 19: 12996152 (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	Jul 30, 2013	Oct 8, 2024	Jun 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006563.5:c.892G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006554.1:p.Ala298Pro	missense
NC_000019.10:g.12885338C>G
NC_000019.9:g.12996152C>G
NG_013087.1:g.6866G>C
NG_068129.1:g.428C>G
NG_068129.2:g.504C>G
LRG_825:g.6866G>C
LRG_825t1:c.892G>C	LRG_825p1:p.Ala298Pro
	Q13351:p.Ala298Pro

... more HGVS ... less HGVS

Protein change

A298P

Other names

Canonical SPDI

NC_000019.10:12885337:C:G

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

ClinGen: CA144518 UniProtKB: Q13351#VAR_072737 OMIM: 600599.0010 dbSNP: rs387907598 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.
KLF1		-	-	GRCh38 GRCh37	51	183
LOC117125591	-	-	-	GRCh38	-	62

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.
BLOOD GROUP--LUTHERAN INHIBITOR Congenital dyserythropoietic anemia type 4 FETAL HEMOGLOBIN QUANTITATIVE TRAIT LOCUS 6	Pathogenic (1)	no assertion criteria provided	-	RCV000050236.2
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 2, 2023	RCV003556137.2
ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVb	Pathogenic (1)	no assertion criteria provided	Oct 3, 2024	RCV004777567.1

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.
Pathogenic (Jun 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004297903.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24443441‚ 34227100 Comment: For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more) For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KLF1 protein function. ClinVar contains an entry for this variant (Variation ID: 56891). This missense change has been observed in individual(s) with autosomal recessive congenital hemolytic anemia (PMID: 24443441, 34227100). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 298 of the KLF1 protein (p.Ala298Pro). (less)
pathogenic (-)	no assertion criteria provided Method: not provided	ANEMIA, DYSERYTHROPOIETIC CONGENITAL, TYPE IV BLOOD GROUP--LUTHERAN INHIBITOR Fetal hemoglobin quantitative trait locus 6 Affected status: not provided Allele origin: unknown	Department of Medical Genetics, Oslo University Hospital Accession: SCV000082828.1 First in ClinVar: Jul 30, 2013 Last updated: Jul 30, 2013 Comment: anemia	Comment: Converted during submission to Pathogenic.
Pathogenic (Oct 03, 2024)	no assertion criteria provided Method: literature only	ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVb Affected status: not provided Allele origin: germline	OMIM Accession: SCV005367938.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Publications: PubMed (1) PubMed: 24443441 Comment on evidence: In 4 unrelated patients (P5, P6, P7, and P8) with congenital dyserythropoietic anemia type IVb (CDAN4B; 620969), Viprakasit et al. (2014) identified compound heterozygous mutations … (more) In 4 unrelated patients (P5, P6, P7, and P8) with congenital dyserythropoietic anemia type IVb (CDAN4B; 620969), Viprakasit et al. (2014) identified compound heterozygous mutations in exon 2 of the KLF1 gene: a c.892G-C transversion, resulting in an ala298-to-pro (A298P) substitution at a highly conserved residue in the ZF1 domain, and a 7-bp insertion (c.525_526insCGGCGCC; 600599.0011), resulting in a frameshift and premature termination (Gly176ArgfsTer179) in the transactivating domain. Another patient (P3) was compound heterozygous for A298P and a -154C-T transition 5-prime of the initiating ATG codon (600599.0012), and another (P4) was compound heterozygous for A298P and a c.172C-T transition in exon 2, resulting in a gln58-to-ter (Q58X; 600599.0014) substitution in the transactivating domain. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KLF1 protein function. ClinVar contains an entry for this variant (Variation ID: 56891). This missense change has been observed in individual(s) with autosomal recessive congenital hemolytic anemia (PMID: 24443441, 34227100). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 298 of the KLF1 protein (p.Ala298Pro).

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
Severe neonatal haemolytic anaemia caused by compound heterozygous KLF1 mutations: report of four families and literature review.	Tangsricharoen T	British journal of haematology	2021	PMID: 34227100
Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression.	Viprakasit V	Blood	2014	PMID: 24443441

Text-mined citations for rs387907598 ...

These 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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_006563.5(KLF1):c.892G>C (p.Ala298Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs387907598 ...