NM_000518.5(HBB):c.20A>T (p.Glu7Val) AND Beta-thalassemia HBB/LCRB

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 22, 2022
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:: RCV002288496.12

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]

Observations:

Condition(s)

Name:: Beta-thalassemia HBB/LCRB
Identifiers:: MONDO: MONDO:0013517; MedGen: CN322236; OMIM: 613985

Recent activity

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rab-like protein 2A isoform X13 [Homo sapiens]
rab-like protein 2A isoform X13 [Homo sapiens]
gi|2217325195|ref|XP_047299019.1|

Protein
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 X33, mRNA
gi|2462569602|ref|XM_054340291.1|

Nucleotide
rab-like protein 2A isoform X2 [Homo sapiens]
rab-like protein 2A isoform X2 [Homo sapiens]
gi|2217325151|ref|XP_047298999.1|

Protein
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 X13, mRNA
gi|2217325159|ref|XM_017003215.2|

Nucleotide
rab-like protein 2A isoform X4 [Homo sapiens]
rab-like protein 2A isoform X4 [Homo sapiens]
gi|2462569561|ref|XP_054196245.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002556466	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 6, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002581124	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005060996	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005196600	MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	no assertion criteria provided	Pathogenic (May 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
Southeast Asian	germline	yes	39	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

Compound heterozygosity for hemoglobin S and hemoglobin E in a family of Proto-Australoid origin: a case report.

Basumatary N, Baruah D, Sarma PK, Sarmah J.

J Med Case Rep. 2021 Aug 2;15(1):386. doi: 10.1186/s13256-021-02974-4.

PubMed [citation]

PMID:: 34334128
PMCID:: PMC8327456

Details of each submission

From Genetics and Molecular Pathology, SA Pathology, SCV002556466.2

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

From MGZ Medical Genetics Center, SCV002581124.1

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005060996.1

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

Description

The missense c.20A>T (p.Glu7Val) variant in HBB gene has been reported previously in homozygous and compound heterozygous state in multiple individuals affected with HBB-related sickle cell anemia (Akinbami et al. 2016; Meher et al. 2016). Experimental studies have shown that this mutation (Glu7Val) in hemoglobin (Hb) causes red blood cells to assume a rigid curved shape that blocks their passage through the vasculature resulting in ischemia, severe pain, and necrosis (Eshbach et al. 2017). The p.Glu7Val variant has 0.4% allele frequency in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid change p.Glu7Val in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glutamic acid at position 7 is changed to a Valine changing protein sequence and it might alter its composition and physico-chemical properties. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN, SCV005196600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Southeast Asian	39	not provided	not provided	clinical testing	PubMed (1)

Description

The variant HBB:c.20A>T [NP_000509.1:p.Glu7Val ] , produce sickle hemoglobin (HbS), it is a beta+ mutation. Homozygous of this variant is responsible for sickle cell anaemia . In combination with other beta mutation it may cause wide variety of sickle beta phenotype. The frequency of this allele in different state of India varies from 2 % to 20% (Ref: PMID: 30523337] . The frequency of this variant among hemoglobinopathy patient in West Bengal is less than 3.8 % as per multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations, Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018].

#	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		39	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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