ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.20A>T (p.Glu7Val) (rs334)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224000 SCV000603887 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The Hb S variant (HBB: c.20A>T, Glu6Val) is a common pathogenic beta globin (HBB) 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 for Hb S:
Ambry Genetics RCV000623118 SCV000741189 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000723337 SCV000854734 pathogenic Fetal hemoglobin quantitative trait locus 1 2018-07-19 no assertion criteria provided clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224000 SCV000281507 pathogenic not provided 2014-09-15 criteria provided, single submitter clinical testing
Counsyl RCV000576548 SCV000678040 pathogenic beta Thalassemia 2015-09-30 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477892 SCV000536833 pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; Susceptibility to malaria; beta Thalassemia 2016-02-23 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224000 SCV000224235 pathogenic not provided 2014-12-19 criteria provided, single submitter clinical testing
GeneDx RCV000224000 SCV000321760 pathogenic not provided 2018-10-24 criteria provided, single submitter clinical testing The E7V pathogenic variant in the HBB gene, also commonly referred to as E6V due to the use of alternative nomenclature, results in the production of HbS and has been reported previously in association with sickle cell anemia when present in the homozygous state (Bender, 2017). The E7V variant is the most common variant associated with sickle cell disease in African American individuals with an allele frequency of 4% (Tabor et al., 2014). The E7V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies using transgenic mouse models showed mouse erythrocytes with the E7V variant sickled upon deoxygenation (Greaves et al., 1990). We interpret E7V as a pathogenic variant.
GeneReviews RCV000016574 SCV000190688 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only
Genetic Services Laboratory, University of Chicago RCV000016574 SCV000247542 pathogenic Hb SS disease 2015-02-16 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000224000 SCV000809296 pathogenic not provided 2018-09-16 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000016574 SCV000584093 pathogenic Hb SS disease 2018-04-16 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000016574 SCV000914520 pathogenic Hb SS disease 2017-04-27 criteria provided, single submitter clinical testing The HBB c.20A>T (p.Glu7Val) missense variant, also described as p.Glu6Val, is the singular cause of hemoglobin S (Hb S). Individuals who are heterozygous for this variant are said to carry the sickle cell trait. Across a selection of available literature, the p.Glu7Val variant was identified in a homozygous state in at least 1,032 individuals who were diagnosed with sickle cell disease (Kondani et al. 2014; Shrikhande et al. 2014; Grosse et al. 2016). Kondani et al. (2014) reported that of 247 Congolese children studied, the 19 children who were diagnosed with sickle cell anemia were all homozygous for the p.Glu7Val variant, while those without the disease did not carry the variant. In a community screening program of the HBB gene in 35,636 Indian individuals, Shrikhande et al. (2014) identified 5,466 individuals who were heterozygous for the p.Glu7Val variant and 1,010 individuals who were homozygous and who had sickle cell disease. The p.Glu7Val variant is reported at a frequency of 0.13889 in the Yoruba in Ibadan, Nigeria population of the 1000 Genomes Project. Based on the collective evidence, the p.Glu7Val variant is classified as pathogenic for sickle cell disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000224000 SCV000949988 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 7 of the HBB protein (p.Glu7Val). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is present in population databases (rs334, ExAC 5%). This is a common, well-known variant that has been observed in individuals affected with sickle cell disease (PMID: 20301551, 20861612, 19758965, 26372199). It is also known as p.Glu6Val and HbS in the literature. ClinVar contains an entry for this variant (Variation ID: 15333). Experimental studies have shown that this missense change affects hemoglobin polymerization and can result in abnormally-shaped red blood cells (PMID: 12124399, 28356267, 1802884). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000016574 SCV000967671 pathogenic Hb SS disease 2017-04-25 criteria provided, single submitter clinical testing The 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,; 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.
OMIM RCV000016573 SCV000036842 other HEMOGLOBIN S 2019-07-16 no assertion criteria provided literature only
OMIM RCV000016574 SCV000036843 pathogenic Hb SS disease 2019-07-16 no assertion criteria provided literature only
OMIM RCV000016575 SCV000036844 protective Malaria, resistance to 2011-12-02 no assertion criteria provided literature only

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