NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 4, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002227042.12

Allele description [Variation Report for NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln)]

NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln)

Gene:

SLC4A1:solute carrier family 4 member 1 (Diego blood group) [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_000342.3(SLC4A1):c.2279G>A (p.Arg760Gln)

HGVS:

NC_000017.11:g.44253150C>T
NG_007498.1:g.19985G>A
NM_000342.4:c.2279G>AMANE SELECT
NP_000333.1:p.Arg760Gln
LRG_803t1:c.2279G>A
LRG_803:g.19985G>A
LRG_803p1:p.Arg760Gln
NC_000017.10:g.42330518C>T
P02730:p.Arg760Gln

Protein change:

R760Q; ARG760GLN

Links:

UniProtKB: P02730#VAR_013806; OMIM: 109270.0028; dbSNP: rs121912755

NCBI 1000 Genomes Browser:

rs121912755

Molecular consequence:

NM_000342.4:c.2279G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002506120	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely pathogenic (Apr 21, 2023)	germline	clinical testing	Citation Link,
SCV003819121	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 14, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004298223	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7530501, 32641076, 11208088, 23842529, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002506120

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Likely pathogenic
(Apr 21, 2023)

germline

clinical testing

Citation Link,

SCV003819121

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 14, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004298223

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 4, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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, Rubin HL, Brabec V, Chrobak L, Zolotarev AS, Alper SL, Brugnara C, Wichterle H, Palek J.

Blood. 1995 Feb 1;85(3):634-40.

PubMed [citation]

PMID:: 7530501

See all PubMed Citations (6)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002506120.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The SLC4A1 c.2279G>A; p.Arg760Gln variant (rs121912755), also known as Band 3 Prague II, is reported in the literature in individuals affected with hereditary spherocytosis (Bruce 2005, Fermo 2021, Jarolim 1995, Van Zwieten 2013, Vercellati 2022, Yawata 2001). This variant is also reported in ClinVar (Variation ID: 17780). Functional analyses show that the variant protein is not incorporated into the cell membrane of erythrocytes and is associated with abnormal membrane permeability and ion fluxes (Bruce 2005, Jarolim 1995, Quilty 2000). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.898). Based on available information, this variant is considered to be likely pathogenic. REFERENCES Bruce LJ et al. Monovalent cation leaks in human red cells caused by single amino-acid substitutions in the transport domain of the band 3 chloride-bicarbonate exchanger, AE1. Nature genetics. 2005 Nov. PMID: 16227998 Fermo E et al. Targeted Next Generation Sequencing and Diagnosis of Congenital Hemolytic Anemias: A Three Years Experience Monocentric Study. Front Physiol. 2021 PMID: 34093240 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 Van Zwieten R et al. Hereditary spherocytosis due to band 3 deficiency: 15 novel mutations in SLC4A1. Am J Hematol. 2013 Feb. PMID: 23255290 Vercellati C et al. Effect of primary lesions in cytoskeleton proteins on red cell membrane stability in patients with hereditary spherocytosis. Front Physiol. 2022 PMID: 36035481 Yawata Y et al. Hereditary Red Cell Membrane Disorders in Japan: Their Genotypic and Phenotypic Features in 1014 Cases Studied. Hematology. 2001 PMID: 27405697

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003819121.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298223.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 760 of the SLC4A1 protein (p.Arg760Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with spherocytosis (PMID: 7530501, 32641076). ClinVar contains an entry for this variant (Variation ID: 17780). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 11208088, 23842529). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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