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

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Oct 18, 2019
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:: RCV000576548.24

Allele description [Variation Report for NM_000518.5(HBB):c.20A>T (p.Glu7Val)]

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]

Condition(s)

Name:: beta Thalassemia (BTHAL)
Synonyms:: Cooley's anemia; Erythroblastic anemia; Mediterranean anemia
Identifiers:: MONDO: MONDO:0019402; MedGen: C0005283; Orphanet: 848

Recent activity

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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 X23, mRNA
gi|2462569584|ref|XM_054340282.1|

Nucleotide
rab-like protein 2A isoform X8 [Homo sapiens]
rab-like protein 2A isoform X8 [Homo sapiens]
gi|2462569585|ref|XP_054196257.1|

Protein
rab-like protein 2A isoform X7 [Homo sapiens]
rab-like protein 2A isoform X7 [Homo sapiens]
gi|2462569581|ref|XP_054196255.1|

Protein
Homo sapiens RAB, member of RAS oncogene family like 2A (RABL2A), transcript var...
Homo sapiens RAB, member of RAS oncogene family like 2A (RABL2A), transcript variant 4, mRNA
gi|1677537711|ref|NM_001306159.2|

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 X8, mRNA
gi|2462569554|ref|XM_054340267.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001138222	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001142414	Reproductive Health Research and Development, BGI Genomics	no assertion criteria provided	Pathogenic (Jan 6, 2020)	germline	curation
SCV001194011	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Oct 18, 2019)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19061217, 2582106, 22028795, 22625666, 22010933, 2888754, 20954261, 6583683, 1376298 Citation Link,
SCV002091614	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV002767565	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 28, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003931163	GenomeConnect - Brain Gene Registry	no classification provided	not provided	paternal	phenotyping only

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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, curation
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	unknown	1	not provided	not provided	1	not provided	phenotyping only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Newborn screening for hemoglobinopathies in California.

Michlitsch J, Azimi M, Hoppe C, Walters MC, Lubin B, Lorey F, Vichinsky E.

Pediatr Blood Cancer. 2009 Apr;52(4):486-90. doi: 10.1002/pbc.21883.

PubMed [citation]

PMID:: 19061217
PMCID:: PMC4755934

Clinical presentation of homozygous sickle cell disease.

Bainbridge R, Higgs DR, Maude GH, Serjeant GR.

J Pediatr. 1985 Jun;106(6):881-5.

PubMed [citation]

PMID:: 2582106

See all PubMed Citations (10)

Details of each submission

From Mendelics, SCV001138222.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Reproductive Health Research and Development, BGI Genomics, SCV001142414.1

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

Description

NM_000518.4:c.20A>T is also known as p.Glu6Lys or HbS in the literature. NM_000518.4:c.20A>T in the HBB gene has an allele frequency of 0.045 in African subpopulation in the gnomAD database. The c.20A>T (p.Glu7Val) variant in HBB is the most prevalent genotype associated with sickle cell disease (PMID: 25203083). Kondani et al reported that among 247 children, 19 (7.7%) were homozygous sickle cell anemia patients (Hb SS) (PMID: 25023084). Experimental studies have shown that this missense change affects hemoglobin polymerization and can result in abnormally-shaped red blood cells (PMID: 12124399; 28356267; 1802884). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PM3; PP4.

#	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 Myriad Genetics, Inc., SCV001194011.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

NM_000518.4(HBB):c.20A>T(E7V, aka Hb S) is classified as pathogenic and is associated with hemoglobin S (sickle cell disease). Sources cited for classification include the following: PMID 19061217, 2582106, 22028795, 22625666, 22010933, 2888754, 20954261, 6583683, 1376298. Classification of NM_000518.4(HBB):c.20A>T(E7V, aka Hb S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£

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

From Natera, Inc., SCV002091614.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767565.1

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

Description

A heterozygous missense variant, NM_000518.5(HBB):c.20A>T, has been identified in exon 1 of 3 of the HBB gene. The variant is predicted to result in a major amino acid change from glutamic acid to valine at position 7 of the protein (NP_000509.1(HBB):p.(Glu7Val)). The glutamic acid at this position has low conservation (100 vertebrates, UCSC), and is located within the Hb-beta like functional domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.4% (1228 heterozygous, 4 homozygous). An alternative residue change has been reported in the gnomAD database at a frequency of 0.1%. The variant is the cause of hemoglobin S which results in sickle cell anemia and has been previously described as pathogenic and segregated with disease in multiple families (ClinVar; Kwiatkowski, D.P. 2005). Even though often fatal when homozygous or compound heterozygous, it is seen in high frequency (~10%) in populations in Sub-Saharan African and Middle East where it has been positively selected because it confers protection against malaria in heterozygous individuals, which are asymptomatic (Kwiatkowski, D.P. 2005). Additionally, functional studies showed that erythrocytes from transgenic mice expressing human HBB sickle readily on deoxygenation (Greaves, D.R. et al., 1990). A different variant in the same codon resulting in a change to lysine has been reported to cause a mild hemolytic anemia (ClinVar; Kwiatkowski, D.P. 2005). Based on the information available at the time of curation, 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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect - Brain Gene Registry, SCV003931163.1

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

Description

Variant classified as Pathogenic and reported on 02-03-2017 by Baylor Medical Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.

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

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine