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rs334

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 12P and 5B. PM1PM5PP5_Very_StrongBP4BS2

The NM_000518.5(HBB):c.20A>T(p.Glu7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 152176 control chromosomes in the gnomAD Genomes database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 9 hom., cov: 32)
Exomes 𝑓: 0.0035 ( 3 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

2
3
12

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:53B:1O:4

Conservation

PhyloP100: 0.690

Links

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 12 uncertain in NM_000518.5
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr11-5227003-C-T is described in ClinVar as [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 15126. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=23, Benign=1}.
PP5
?
Variant 11-5227002-T-A is Pathogenic according to our data. Variant chr11-5227002-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 15333. Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227002-T-A is described in Lovd as [Pathogenic]. Variant chr11-5227002-T-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.007841617).. Strength limited to SUPPORTING due to the PP5.
BS2
?
High Homozygotes in GnomAd at 9 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.20A>T p.Glu7Val missense_variant 1/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.20A>T p.Glu7Val missense_variant 1/31 NM_000518.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0127
AC:
1926
AN:
152176
Hom.:
9
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0434
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00228
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00718
GnomAD3 exomes
AF:
0.00348
AC:
874
AN:
251180
Hom.:
3
AF XY:
0.00266
AC XY:
361
AN XY:
135742
show subpopulations
Gnomad AFR exome
AF:
0.0470
Gnomad AMR exome
AF:
0.00217
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000621
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00163
GnomAD4 exome
AF:
0.00160
AC:
2335
AN:
1458356
Hom.:
31
AF XY:
0.00145
AC XY:
1054
AN XY:
725764
show subpopulations
Gnomad4 AFR exome
AF:
0.0569
Gnomad4 AMR exome
AF:
0.00244
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000316
Gnomad4 OTH exome
AF:
0.00333
Alfa
AF:
0.000785
Hom.:
0
ESP6500AA
AF:
0.0402
AC:
177
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00439
AC:
533
Asia WGS
AF:
0.0130
AC:
47
AN:
3476
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:53Benign:1Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hb SS disease Pathogenic:20Other:1
Pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015333, PMID:3267215, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 25023084, 25203083, 25023085, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 1802884, 2296310, 28356267, 12124399, PS3_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23591685, 29542687, PM3_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015126,VCV000036301, PMID:19460936,6129204,8294201, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.83, PP3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyApr 16, 2018- -
Pathogenic, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoJan 07, 2022- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsApr 29, 2021- -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalMar 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San DiegoJun 29, 2018The c.20A>T (p.Glu7Val) variant in HBB (also known as p.Glu6Val) is the most prevalent genotype associated with sickle cell disease (PMID: 25203083). This variant is an established disease-associated mutation and has been reported as pathogenic by multiple clinical diagnostic laboratories in ClinVar (variant ID: 15333). Based on the available evidence, the c.20A>T (p.Glu7Val) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 25, 2017The p.Glu7Val variant (also known as Glu6Val and hemoglobin S variant) in HBB ha s been identified in 1088/24028 (4.5%) of African chromosomes by the Genome Aggr egation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77121243). T he p.Glu7Val variant in HBB, in the homozygous state, causes sickle cell anemia, which accounts for 60-70% of sickle cell disease in the US. Co-inheritance with a second HBB variant associated with abnormal hemoglobin (such as Hb C, Hb D, H b O, Hb E and ?-thalassemia pathogenic variants) results in sickle cell disease. -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalMay 09, 2018[ACMG/AMP: PS3, PM3, PM5, PS4_Moderate, PP5] This alteration is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is detected in trans with a known pathogenic variant [PM3], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 06, 2023The HBB c.20A>T (p.Glu7Val) missense variant, also referred to as p.Glu6Val, has been reported in a homozygous state in more than 1000 individuals with sickle cell anemia (PMID: 25023084; 25023085; 26275168). The highest frequency of this allele in the Genome Aggregation Database is 0.04490 in the African/African-American population (version 2.1.1). This frequency is high, however, carriers are hypothesized to confer protection against Plasmodium falciparum malaria infection (PMID: 21045822). In mice expressing the sickle trait variant, erythrocytes were shown to sickle with deoxygenation, similar to that seen in humans with sickle cell anemia (PMID: 2296310), and in mice with 100% expression of the sickle cell variant, chronic hemolytic anemia with circulating sickled erythrocytes, as well as chronic tissue damage, was observed (PMID: 12124399). Based on the available evidence, the c.20A>T (p.Glu7Val) variant is classified as pathogenic for sickle cell disease. -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyFeb 06, 2020PS4, PS3, PP1, PP5, PP4. -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterFeb 10, 2021The c.20A>T (p.Glu7Val) variant in HBB (also known as p.Glu6Val) is the most prevalent genotype associated with sickle cell disease [PMID: 25203083]. This variant is an established disease-associated mutation and has been reported as pathogenic by multiple clinical diagnostic laboratories in ClinVar (variant ID: 15333). This variant is identified in gnomAD in 1826 heterozygous individuals, 9 homozygous individuals, with an allele frequency of 1.27e-2. Based on the available evidence, the c.20A>T (p.Glu7Val) variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 11, 2022This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitterresearchH3Africa ConsortiumOct 12, 2022While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.53, its frequency in African populations is >5%, as there is a high prevalence of sickle cell disease in African ancestry individuals. -
Pathogenic, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 14, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenomics Facility, Ludwig-Maximilians-Universität MünchenDec 28, 2021- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine-The missense c.20A>T (p.Glu7Val) variant in HBB has been reported in homozygous individuals affected with sickle cell anemia and heterozygous state in sickle cell anemia trait. This is a common, well-known variant that has been observed in individuals affected with sickle cell disease (Kutlar, Ferdane et al.,2010 and Bender, MA.,2003). Experimental studies have shown that this missense change affects hemoglobin polymerization and can result in abnormally-shaped red blood cells (He, Zhenning et al.,2002, Eshbach, Megan L et al.,2017). This variant is reported with the allele frequency 0.4% in the gnomAD and 2.7% in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Glu at position 7 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Glu7Val in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanySep 22, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterAug 10, 2022PS3, PS4, PM3, PP1 -
Pathogenic, criteria provided, single submitterclinical testingLifecell International Pvt. Ltd-A Heterozygous Missense variant c.20A>T in Exon 1 of the HBB gene that results in the amino acid substitution p.Glu7Val was identified. The observed variant has a minor allele frequency of 0.00348% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic, Likely Benign, and Conflicting Interpretations (Variant ID: 15333). This variant has previously been reported for sickle cell anemia by Jaripour ME, et, al., 2018. Experimental studies have shown that this missense change affects HBB function by Eshbach ML, et, al, 2017. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -
not provided Pathogenic:15
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 28, 2022The 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 -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalMar 02, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 15, 2014- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2022HBB: PM3:Very Strong, PM2, PP4, BP4 -
Pathogenic, no assertion criteria providedresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, Revvity OmicsOct 29, 2023- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 04, 2022This 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 11, 2022- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsNov 22, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 25, 2021Functional 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) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 19, 2014- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
beta Thalassemia Pathogenic:5Other:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Oct 18, 2019NM_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.‚Äã -
not provided, no classification providedphenotyping onlyGenomeConnect - Brain Gene Registry-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/. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, no assertion criteria providedcurationReproductive Health Research and Development, BGI GenomicsJan 06, 2020NM_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. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteAug 28, 2019A 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. -
HBB-Related Disorders Pathogenic:2Other:1
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-The c.20A>T (p.Glu7Val) variant in HBB, also known as p.Glu6Val, is referred to as the hemoglobin S allele (HbS) and causes autosomal recessive sickle cell disease (MIM: #603903) when it is homozygous or compound heterozygous with a different pathogenic variant. Individuals who are heterozygous for the HbS allele have sickle cell trait (SCT). The c.20A>T (p.Glu7Val) variant is the most prevalent genotype associated with sickle cell disease (PMID: 25203083). This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It is present at a frequency of 0.4% (1236/282580 heterozygotes and 4/282580 homozygotes) in the gnomAD population database. The c.20A>T (p.Glu7Val) variant is an established disease-causing mutation. Based on the available evidence, c.20A>T(p.Glu7Val) is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingDASAMar 05, 2022Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 13464827; 11880644; 11830454; 12124399; 28356267; 1802884) - PS3.The c.20A>T;p.(Glu7Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 15333; PMID: 20301551; PMID: 30002798; PMID: 15658184;PMID: 7384810; PMID: 6268660; PMID: 26372199; PMID: 26275168; PMID: 28356267; PMID: 22625666; PMID: 32527859) - PS4. The p.(Glu7Val) was detected in trans with a pathogenic variant (PMID: 15658184; PMID: 20861612; PMID: 21131035) - PM3_very strong. Pathogenic missense variant in this residue have been reported (ClinVar ID: 15126 PMID: 20301551; 27117572; 26372199) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 21302591; 34334128; 14084634; 26041415) - PP1_strong.and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is pathogenic. -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant identified in multiple registry participants. Variant interpreted as consistent with alpha thalassemia trait and reported on 02-28-2020 by Lab or GTR ID 500068. Variant interpreted as Pathogenic and reported on 07-21-2020 by Lab or GTR ID 1197. Variant interpreted as Pathogenic and reported on 05-26-2021 by Lab or GTR ID 20290. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Beta-thalassemia HBB/LCRB Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 22, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologySep 06, 2019- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2014Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected -
Sickle cell-hemoglobin C disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityFeb 17, 2023This HBB variant (rs334) reaches polymorphic frequency (>1%) within the African/African American subpopulation in a large population dataset (gnomAD: 1121/24964 total alleles; 4.49%; 4 homozygotes) and has been reported in ClinVar. It is the most common pathogenic HBB variant in individuals of African ancestry. Also known as p.Glu6Val and HbS, it has been reported in a homozygous or compound heterozygous state in individuals with beta-hemoglobinopathies. One bioinformatic tool queried predicts that this substitution would damaging, while another predicts it would be tolerated. Experimental studies have shown that this variant affects the physical and kinetic properties of the hemoglobin protein. Bioinformatic analysis predicts that this missense variant would not affect normal exon 1 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.20A>T (p.Glu7Val) to be pathogenic. -
Anemia Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingNew York Genome CenterJan 16, 2020- -
alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 30, 2021- -
Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to Pathogenic:1
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaFeb 23, 2016- -
Fetal hemoglobin quantitative trait locus 1 Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityJul 19, 2018- -
See cases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinJan 06, 2022ACMG classification criteria: PS3, PS4, PM3, BS1 -
Sickle cell disease and related diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 14, 2019Variant summary: HBB c.20A>T (p.Glu7Val) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 251180 control chromosomes in the gnomAD database, including 3 homozygotes. c.20A>T has been reported in the literature in multiple individuals affected with Sickle Cell Disease, an inherited monogenic disease characterized by intravascular sickling, haemolysis, anemia and leukocytosis as well as the association between sickled red blood cells and other blood components (example, Domingos_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in decreased solubility of deoxygenated Hb S, and polymerization which leads to the formation of an extensive network of fibers in red blood cells (example, Adachi_1991). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
HBB-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, Part of Exact SciencesSep 18, 2023The HBB c.20A>T variant is predicted to result in the amino acid substitution p.Glu7Val. This variant, also referred to as p.Glu6Val using legacy nomenclature, has previously been reported to be causative for sickle cell anemia when present in the homozygous state (Engelke et al. 1988. PubMed ID: 3267215; Bender et al. 2017. PubMed ID: 20301551). Individuals heterozygous for this variant have sickle cell trait and are usually asymptomatic but can be at risk for complications (Key and Derebail. 2010. PubMed ID: 21239829). This variant is reported in 4.5% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-5248232-T-A). We interpret this variant as pathogenic. -
Malaria, resistance to Benign:1
protective, no assertion criteria providedliterature onlyOMIMDec 02, 2011- -
HEMOGLOBIN S Other:1
other, no assertion criteria providedliterature onlyOMIMNov 14, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Uncertain
0.0
Cadd
Benign
13
Dann
Benign
0.96
DEOGEN2
Benign
0.11
T;T;.;T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.40
N
MetaRNN
Benign
0.0078
T;T;T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Pathogenic
3.6
H;H;.;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.38
T
PROVEAN
Pathogenic
-4.8
D;.;.;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.025
D;.;.;D
Sift4G
Benign
0.063
T;.;.;.
Polyphen
0.0010
B;B;.;.
Vest4
0.54
MVP
0.95
MPC
0.037
ClinPred
0.049
T
GERP RS
0.15
Varity_R
0.51
gMVP
0.63

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs334; hg19: chr11-5248232; API