The SLC4A1 c.2608C>T; p.Arg870Trp variant (rs28931585), also known as band 3 Prague III, is reported in the literature in three individuals affected with spherocytosis (Andolfo 2021, Bracher 2001, Jarolim 1995). In vitro functional analyses demonstrate that the mutant protein is unable to incorporate into cell membranes (Quilty 2000). This variant is also reported in ClinVar (Variation ID: 17776). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 870 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.907). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Andolfo I et al. Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients. Genes (Basel). 2021 Jun 23. PMID: 34201899 Bracher NA et al. Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III. Br J Haematol. 2001 Jun. PMID: 11380459 Jarolim P et al. Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood. 1995 Feb 1. PMID: 7530501 Quilty JA et al. Trafficking and folding defects in hereditary spherocytosis mutants of the human red cell anion exchanger. Traffic. 2000 Dec. PMID: 11208088
ClinVar Genomic variation as it relates to human health
NM_000342.3(SLC4A1):c.2608C>T (p.Arg870Trp)
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.
(6)
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.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000342.3(SLC4A1):c.2608C>T (p.Arg870Trp)
Variation ID: 17776 Accession: VCV000017776.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.31 17: 44251206 (GRCh38) [ NCBI UCSC ] 17: 42328574 (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 Aug 22, 2016 Oct 20, 2024 Jul 24, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000342.4:c.2608C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000333.1:p.Arg870Trp missense NC_000017.11:g.44251206G>A NC_000017.10:g.42328574G>A NG_007498.1:g.21929C>T LRG_803:g.21929C>T LRG_803t1:c.2608C>T LRG_803p1:p.Arg870Trp P02730:p.Arg870Trp - Protein change
- R870W
- Other names
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- Canonical SPDI
- NC_000017.11:44251205:G:A
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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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- 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. |
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| SLC4A1 | - | - |
GRCh38 GRCh37 |
688 | 700 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2001 | RCV000019354.30 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV001093444.40 |
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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Likely pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002506101.3
First in ClinVar: May 07, 2022 Last updated: Feb 20, 2024 |
Comment:
The SLC4A1 c.2608C>T; p.Arg870Trp variant (rs28931585), also known as band 3 Prague III, is reported in the literature in three individuals affected with spherocytosis (Andolfo … (more)
The SLC4A1 c.2608C>T; p.Arg870Trp variant (rs28931585), also known as band 3 Prague III, is reported in the literature in three individuals affected with spherocytosis (Andolfo 2021, Bracher 2001, Jarolim 1995). In vitro functional analyses demonstrate that the mutant protein is unable to incorporate into cell membranes (Quilty 2000). This variant is also reported in ClinVar (Variation ID: 17776). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 870 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.907). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Andolfo I et al. Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients. Genes (Basel). 2021 Jun 23. PMID: 34201899 Bracher NA et al. Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III. Br J Haematol. 2001 Jun. PMID: 11380459 Jarolim P et al. Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood. 1995 Feb 1. PMID: 7530501 Quilty JA et al. Trafficking and folding defects in hereditary spherocytosis mutants of the human red cell anion exchanger. Traffic. 2000 Dec. PMID: 11208088 (less)
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Likely pathogenic
(Jan 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713722.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PM2, PP3, PP5
Number of individuals with the variant: 1
|
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Likely pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238672.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442386.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 870 of the SLC4A1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 870 of the SLC4A1 protein (p.Arg870Trp). 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 SLC4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17776). This variant is also known as Prague III. This missense change has been observed in individuals with autosomal dominant hereditary spherocytosis (PMID: 7530501, 23255290). This variant is not present in population databases (gnomAD no frequency). (less)
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Likely pathogenic
(Aug 01, 2019)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250429.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2001)
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no assertion criteria provided
Method: literature only
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SPHEROCYTOSIS, TYPE 4, DUE TO BAND 3 PRAGUE III
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039644.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Bracher et al. (2001) described a case of severe spherocytosis (SPH4; 612653) due to compound heterozygosity for an E90K mutation (109270.0023) and the CGG-to-TGG band-3 … (more)
Bracher et al. (2001) described a case of severe spherocytosis (SPH4; 612653) due to compound heterozygosity for an E90K mutation (109270.0023) and the CGG-to-TGG band-3 Prague III mutation in exon 19 of the SLC4A1 gene, arg870 to trp (R870W), previously described by Jarolim et al. (1995). The mother had a normal blood count, osmotic fragility, and peripheral blood smear; the father was unknown. The child displayed no jaundice and did not have splenomegaly. (less)
|
Comment:
Comment:
PS3, PM2, PP3, PP5
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 870 of the SLC4A1 protein (p.Arg870Trp). 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 SLC4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17776). This variant is also known as Prague III. This missense change has been observed in individuals with autosomal dominant hereditary spherocytosis (PMID: 7530501, 23255290). This variant is not present in population databases (gnomAD no frequency).
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 SLC4A1 c.2608C>T; p.Arg870Trp variant (rs28931585), also known as band 3 Prague III, is reported in the literature in three individuals affected with spherocytosis (Andolfo 2021, Bracher 2001, Jarolim 1995). In vitro functional analyses demonstrate that the mutant protein is unable to incorporate into cell membranes (Quilty 2000). This variant is also reported in ClinVar (Variation ID: 17776). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 870 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.907). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Andolfo I et al. Complex Modes of Inheritance in Hereditary Red Blood Cell Disorders: A Case Series Study of 155 Patients. Genes (Basel). 2021 Jun 23. PMID: 34201899 Bracher NA et al. Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III. Br J Haematol. 2001 Jun. PMID: 11380459 Jarolim P et al. Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. Blood. 1995 Feb 1. PMID: 7530501 Quilty JA et al. Trafficking and folding defects in hereditary spherocytosis mutants of the human red cell anion exchanger. Traffic. 2000 Dec. PMID: 11208088
Comment:
PS3, PM2, PP3, PP5
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 870 of the SLC4A1 protein (p.Arg870Trp). 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 SLC4A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17776). This variant is also known as Prague III. This missense change has been observed in individuals with autosomal dominant hereditary spherocytosis (PMID: 7530501, 23255290). This variant is not present in population databases (gnomAD no frequency).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Band 3, the human red cell chloride/bicarbonate anion exchanger (AE1, SLC4A1), in a structural context. | Reithmeier RA | Biochimica et biophysica acta | 2016 | PMID: 27058983 |
| Hereditary spherocytosis due to band 3 deficiency: 15 novel mutations in SLC4A1. | Van Zwieten R | American journal of hematology | 2013 | PMID: 23255290 |
| Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III. | Bracher NA | British journal of haematology | 2001 | PMID: 11380459 |
| Trafficking and folding defects in hereditary spherocytosis mutants of the human red cell anion exchanger. | Quilty JA | Traffic (Copenhagen, Denmark) | 2000 | PMID: 11208088 |
| Mutations of conserved arginines in the membrane domain of erythroid band 3 lead to a decrease in membrane-associated band 3 and to the phenotype of hereditary spherocytosis. | Jarolim P | Blood | 1995 | PMID: 7530501 |
Text-mined citations for rs28931585 ...
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 Oct 20, 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.