ClinVar Miner

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

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224000 SCV000224235 pathogenic not provided 2014-12-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000016574 SCV000247542 pathogenic Hb SS disease 2015-02-16 criteria provided, single submitter 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
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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000016574 SCV000584093 pathogenic Hb SS disease 2018-04-16 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999922 SCV000603887 pathogenic not specified 2018-07-02 criteria provided, single submitter clinical testing The Hb S variant (HBB: c.20A>T; p.Glu7Val, also known as Glu6Val when numbered from the mature protein) 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 for Hb S: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=226
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
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 2020-01-03 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, 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000016574 SCV000996163 pathogenic Hb SS disease 2018-06-29 criteria provided, single submitter clinical testing The 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.
Mendelics RCV000576548 SCV001138222 pathogenic beta Thalassemia 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000016574 SCV001163295 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000576548 SCV001194011 pathogenic beta Thalassemia 2019-10-18 criteria provided, single submitter clinical testing 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.‚Äã
Illumina Clinical Services Laboratory,Illumina RCV001104054 SCV001260881 likely benign Hemoglobin E 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000576548 SCV001260882 likely benign beta Thalassemia 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000723337 SCV001260883 likely benign Fetal hemoglobin quantitative trait locus 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV001192494 SCV001360653 pathogenic Sickle cell disease and related diseases 2019-10-14 criteria provided, single submitter clinical testing Variant 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.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000016574 SCV001423600 pathogenic Hb SS disease 2018-05-09 criteria provided, single submitter clinical testing [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].
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
GeneReviews RCV000016574 SCV000190688 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only
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
Gharavi Laboratory,Columbia University RCV000224000 SCV000809296 pathogenic not provided 2018-09-16 no assertion criteria provided research
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
Reproductive Health Research and Development,BGI Genomics RCV000576548 SCV001142414 pathogenic beta Thalassemia 2020-01-06 no assertion criteria provided curation 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.
New York Genome Center RCV001255121 SCV001431215 pathogenic Anemia 2020-01-16 no assertion criteria provided clinical testing

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