NM_000518.5(HBB):c.20A>T (p.Glu7Val) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (17 submissions)
Last evaluated:: Aug 1, 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:: RCV000224000.61

Allele description

NM_000518.5(HBB):c.20A>T (p.Glu7Val)

Genes:

LOC106099062:HBB recombination region [Gene]
HBB:hemoglobin subunit beta [Gene - OMIM - HGNC]
LOC107133510:origin of replication at HBB [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000518.5(HBB):c.20A>T (p.Glu7Val)

Other names:

E6V; HbS

HGVS:

NC_000011.10:g.5227002T>A
NG_000007.3:g.70614A>T
NG_042296.1:g.533T>A
NG_046672.1:g.4937T>A
NG_059281.1:g.5070A>T
NM_000518.5:c.20A>TMANE SELECT
NP_000509.1:p.Glu7Val
NP_000509.1:p.Glu7Val
LRG_1232t1:c.20A>T
LRG_1232:g.5070A>T
LRG_1232p1:p.Glu7Val
NC_000011.9:g.5248232T>A
NM_000518.4:c.20A>T
P68871:p.Glu7Val

Protein change:

E7V; Glu6Val

Links:

Genetic Testing Registry (GTR): GTR000500319; UniProtKB: P68871#VAR_002863; OMIM: 141900.0039; OMIM: 141900.0040; OMIM: 141900.0243; OMIM: 141900.0244; OMIM: 141900.0245; OMIM: 141900.0246; OMIM: 141900.0247; OMIM: 141900.0521; OMIM: 141900.0523; dbSNP: rs334

NCBI 1000 Genomes Browser:

rs334

Molecular consequence:

NM_000518.5:c.20A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

249

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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rab-like protein 2A isoform X13 [Homo sapiens]
rab-like protein 2A isoform X13 [Homo sapiens]
gi|2462569601|ref|XP_054196265.1|

Protein
PREDICTED: Rattus norvegicus unc-50 inner nuclear membrane RNA binding protein (...
PREDICTED: Rattus norvegicus unc-50 inner nuclear membrane RNA binding protein (Unc50), transcript variant X2, mRNA
gi|2678969187|ref|XM_006244737.5|

Nucleotide
beta-defensin 43 precursor [Mus musculus]
beta-defensin 43 precursor [Mus musculus]
gi|84993767|ref|NP_001034210.1|

Protein
Eidolon bat coronavirus isolate PL026FS-OS_NGR_2021 RNA-dependent RNA polymerase...
Eidolon bat coronavirus isolate PL026FS-OS_NGR_2021 RNA-dependent RNA polymerase gene, partial cds
gi|2321491685|gb|OM869922.1|

Nucleotide
PREDICTED: Homo sapiens RAB, member of RAS oncogene family like 2A (RABL2A), tra...
PREDICTED: Homo sapiens RAB, member of RAS oncogene family like 2A (RABL2A), transcript variant X21, mRNA
gi|2217325172|ref|XM_047443052.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000224235	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 19, 2014)	germline	clinical testing	Citation Link,
SCV000281507	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 15, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000321760	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 25, 2021)	germline	clinical testing	Citation Link,
SCV000603887	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 29, 2023)	germline	clinical testing	Citation Link,
SCV000809296	Gharavi Laboratory, Columbia University	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000949988	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19758965, 20301551, 20861612, 26372199, 1802884, 12124399, 28356267, 28492532
SCV001450316	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 2, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001714970	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001743401	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001932948	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001955042	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001975550	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002024975	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 29, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002062958	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2024)	germline	clinical testing	Citation Link,
SCV002502707	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 22, 2021)	germline	clinical testing	PubMed (30) [See all records that cite these PMIDs] 3267215, 20981092, 27884173, 1802884, 2888754, 26372199, 19758965, 22028795, 28356267, 20305663, 21329186, 12124399, 19465909, 23065522, 22244832, 20861612, 22975760, 15543018, 23144702, 22010933, 27254408, 30033078, 24123366, 20954261, 31553106, 25087612, 30315176, 22957039, 22625666, 25741868
SCV005090881	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005198430	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	41	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	208	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sickle Cell Disease.

Bender MA, Carlberg K.

2003 Sep 15 [updated 2023 Dec 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301551

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (32)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000224235.3

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

#	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		5	not provided	not provided	not provided

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000281507.1

#	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	not provided	not provided	not provided	not provided		not provided	0.004709	not provided	not provided

From GeneDx, SCV000321760.8

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

Description

Functional studies using transgenic mouse models showed mouse erythrocytes with this variant sickled upon deoxygenation (Greaves et al., 1990) and kinetic studies indicate this variant drastically decreases the molecular stability of the protein (Adachi et al., 1987); Commonly referred to as p.(E6V) due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 20825310, 1802884, 30315176, 3267215, 24123366, 20954261, 22975760, 23065522, 22625666, 19465909, 20305663, 20981092, 22010933, 22028795, 22957039, 23144702, 2296310, 27884173, 27254408, 17393956, 28356267, 26372199, 19758965, 12124399, 22244832, 20861612, 30655275, 30290004, 21329186, 15543018, 30033078, 31553106, 31130284, 31980526, 27650483, 32817264, 32371413, 25023084, 2888754, 31589614, 25087612)

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603887.10

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

Description

The Hb S variant (HBB: c.20A>T; p.Glu7Val, also known as Glu6Val when numbered from the mature protein, HbVar ID: 226, rs334) is a common pathogenic beta globin variant. Heterozygosity for Hb S is consistent with sickle cell trait. Homozygosity for Hb S results in sickle cell anemia. Hb S in combination with a different pathogenic HBB variant on the opposite chromosome results in various forms of sickle cell disease (see HbVar link and references therein). References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html

#	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 Gharavi Laboratory, Columbia University, SCV000809296.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000949988.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 7 of the HBB protein (p.Glu7Val). This variant is present in population databases (rs334, gnomAD 5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with sickle cell disease (PMID: 19758965, 20301551, 20861612, 26372199). This variant is also known as p.Glu6Val and HbS. ClinVar contains an entry for this variant (Variation ID: 15333). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. Experimental studies have shown that this missense change affects HBB function (PMID: 1802884, 12124399, 28356267). For these reasons, this variant has been classified as 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

From Clinical Genetics and Genomics, Karolinska University Hospital, SCV001450316.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	32	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	yes	not provided	not provided	not provided		32	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001714970.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	203	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		203	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001743401.3

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

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001932948.1

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

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955042.1

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

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001975550.1

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

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

From Revvity Omics, Revvity, SCV002024975.3

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002062958.19

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

HBB: PM3:Very Strong, PS3:Moderate, PM2:Supporting, PP4, BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		6	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002502707.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (30)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV005090881.1

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198430.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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