VCV000017752.31 - ClinVar

NM_000342.4(SLC4A1):c.166A>G (p.Lys56Glu)

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.

(12)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000342.4(SLC4A1):c.166A>G (p.Lys56Glu)

Variation ID: 17752 Accession: VCV000017752.31

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 44261577 (GRCh38) [ NCBI UCSC ] 17: 42338945 (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	Aug 22, 2016	Sep 29, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000342.4:c.166A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000333.1:p.Lys56Glu	missense
NC_000017.11:g.44261577T>C
NC_000017.10:g.42338945T>C
NG_007498.1:g.11558A>G
LRG_803:g.11558A>G
LRG_803t1:c.166A>G	LRG_803p1:p.Lys56Glu
	P02730:p.Lys56Glu

... more HGVS ... less HGVS

Protein change

K56E

Other names

SLC4A1, LYS56GLU (rs5036)

Canonical SPDI

NC_000017.11:44261576:T:C

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.

0.06390 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.04243

The Genome Aggregation Database (gnomAD), exomes 0.04461

The Genome Aggregation Database (gnomAD) 0.05002

Trans-Omics for Precision Medicine (TOPMed) 0.05821

1000 Genomes Project 0.06390

1000 Genomes Project 30x 0.06543

Links

ClinGen: CA210832 UniProtKB: P02730#VAR_000799 OMIM: 109270.0001 dbSNP: rs5036 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.
SLC4A1		-	-	GRCh38 GRCh37	700	712

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.
not provided	Pathogenic (1)	no assertion criteria provided	Mar 1, 2009	RCV000019328.38
Autosomal dominant distal renal tubular acidosis	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000357412.13
not specified	Benign (3)	criteria provided, single submitter	-	RCV000251469.17
Hemolytic anemia	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000260217.13
Hereditary spherocytosis type 4	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000989926.13
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV001515404.27

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303732.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Feb 03, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001833287.1 First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021	Comment: This variant is associated with the following publications: (PMID: 29396846, 1520883)
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605167.8 First in ClinVar: Oct 02, 2016 Last updated: Feb 20, 2024
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hereditary spherocytosis type 4 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001140660.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant distal renal tubular acidosis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000403308.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hereditary spherocytosis type 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000403307.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 1520883‚ 8608262 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hemolytic anemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000403309.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jan 29, 2024)	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: SCV001723471.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005212859.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Pathogenic (Mar 01, 2009)	no assertion criteria provided Method: literature only	BAND 3 MEMPHIS Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039618.5 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (7) PubMed: 2146504‚ 893429‚ 2196932‚ 1678289‚ 1419785‚ 1520883‚ 19229254 Comment on evidence: In addition to the variants of band 3 leading to abnormalities of erythrocyte shape (Liu et al., 1990), Mueller and Morrison (1977) identified a polymorphism … (more) In addition to the variants of band 3 leading to abnormalities of erythrocyte shape (Liu et al., 1990), Mueller and Morrison (1977) identified a polymorphism tentatively described as an elongation of the cytoplasmic domain, whose structure was still to be defined. Ranney et al. (1990) found a silent band 3 polymorphism, called band 3 Memphis, in all human populations with a frequency varying from one population to another. Yannoukakos et al. (1991) demonstrated that this electrophoretic variant is due to substitution of glutamic acid for lysine at position 56. An A-to-G substitution in the first base of codon 56 is responsible for the change. Ideguchi et al. (1992) showed that the prevalence of the Memphis variant is particularly high in Japanese; the calculated gene frequency was 0.156, about 4 times higher than in Caucasians. They found that the transport rate of phosphoenolpyruvate in erythrocytes of homozygotes was decreased to about 80% of that in control cells and the rate in heterozygotes was at an intermediate level. They interpreted this as indicating that some structural changes in the cytoplasmic domain of band 3 influence the conformation of the anion transport system. The band 3 Memphis variant is characterized by a reduced mobility of proteolytic fragments derived from the N-terminus of the cytoplasmic domain of band 3 (cdb3). Jarolim et al. (1992) found the AAG-to-GAG transition at codon 56 resulting in the lys56-to-glu substitution in all of 12 heterozygotes including 1 white, 1 black, 1 Chinese, 1 Filipino, 1 Malay, and 7 Melanesian subjects. Since most of the previously cloned mouse, rat, and chicken band 3 and band 3-related proteins contain glutamic acid in the position corresponding to amino acid 56 in the human band 3, Jarolim et al. (1992) proposed that the Memphis variant is the evolutionarily older form of band 3. The Memphis polymorphism is also referred to as rs5036. Wilder et al. (2009) found that all 4 Indonesian chromosomes with the 27-bp deletion (109270.0002) also carried the Memphis polymorphism, suggesting that it is a target of recent natural selection. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928811.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955918.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular population genetics of SLC4A1 and Southeast Asian ovalocytosis.	Wilder JA	Journal of human genetics	2009	PMID: 19229254
Southeast Asian ovalocytosis in a South African kindred with hemolytic anemia.	Coetzer TL	Blood	1996	PMID: 8608262
Band 3 Memphis: a widespread polymorphism with abnormal electrophoretic mobility of erythrocyte band 3 protein caused by substitution AAG----GAG (Lys----Glu) in codon 56.	Jarolim P	Blood	1992	PMID: 1520883
Band 3-Memphis is associated with a lower transport rate of phosphoenolpyruvate.	Ideguchi H	British journal of haematology	1992	PMID: 1419785
Human erythrocyte band 3 polymorphism (band 3 Memphis): characterization of the structural modification (Lys 56----Glu) by protein chemistry methods.	Yannoukakos D	Blood	1991	PMID: 1678289
Frequencies of Band 3 variants of human red cell membranes in some different populations.	Ranney HM	British journal of haematology	1990	PMID: 2196932
Molecular defect of the band 3 protein in southeast Asian ovalocytosis.	Liu SC	The New England journal of medicine	1990	PMID: 2146504
Detection of a variant of protein 3, the major transmembrane protein of the human erythrocyte.	Mueller TJ	The Journal of biological chemistry	1977	PMID: 893429

Text-mined citations for rs5036 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000342.4(SLC4A1):c.166A>G (p.Lys56Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5036 ...