ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.364G>C (p.Glu122Gln) (rs33946267)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV001175348 SCV000052649 pathogenic Hemoglobin D disease 2019-10-18 criteria provided, single submitter clinical testing Variant summary: HBB c.364G>C (p.Glu122Gln) results in a conservative amino acid change in the encoded protein sequence and is a common disease-associated variant. The variant is also cited in the literature as HbD-Los Angeles, HbD-Punjab, HbD-North-Carolina, HbD-Portugal, and HbD-Chicago. 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 0.0007 in 251306 control chromosomes in the gnomAD database, including 4 homozygotes. When found in a homozygous or heterozygous state, c.364G>C is typically associated with either no disease phenotype or very mild anemia (e.g. Politis-Tsegos_1975, Rahimi_2006). However, when found in trans with other thalassemia-associated variants, phenotypes can range from mild to severe anemias and splenomegaly (e.g. Worthington_1985, Fucharoen_2002, Rahimi_2006). In addition, patients with this variant in trans with a pathogenic Hgb S variant may have a severe phenotype similar to Sickle Cell Disease (e.g. Mukherjee_2005). These data indicate that the variant is very likely to be associated with disease. At least one study has reported that the p.Glu122Gln protein may facilitate polymerization of Hgb S (Adachi_1998). Seven other laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014), citing the variant four times as pathogenic, two times as likely pathogenic, and one time as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723826 SCV000331531 pathogenic not provided 2016-02-11 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000029994 SCV000538040 pathogenic beta Thalassemia 2016-01-27 criteria provided, single submitter clinical testing The c.346G>C (p.Glu534Gln) missense variant, Hb D-Los Angeles, is the fourth most common hemoglobin variant world-wide. Multiple reports identify the variant as pathogenic in combination with Hb S. Co-inheritance of Hb D-Los Angeles with Hb S results in Hb SD-Los Angeles (compound heterozygotes) and a moderate to severe clinical phenotype similar to that of sickle cell anemia (SCA). Patients with Hb SD disease have severe hemolytic anemia and recurrent vaso-occlusive episodes. Hb S molecules undergo two-step process leading to nucleation and ultimately the formation of a complex sickle polymer in the deoxygenated state. It is proposed that in the Hb SD-Los Angeles molecule, the Glu122Gln substitution strengthens the second step thereby accelerating polymerization. Thus the Hb D-Los Angeles genotype might increases the probability of sickling (GeneReviews: Origa, 2015, http://www.ncbi.nlm.nih.gov/books/NBK1426/, GeneReviews: Bender et al., 2014, http://www.ncbi.nlm.nih.gov/books/NBK1377/). This missense variant has significantly increased prevalence in affected individuals relative to controls. Individuals who are either heterozygous or homozygous for the Hb D-Los Angeles variant alone are generally asymptomatic, although rarely, Hb D homozygous individuals can present with mild hemolytic anemia and mild to moderate splenomegaly (GeneReviews: Origa, 2015, http://www.ncbi.nlm.nih.gov/books/NBK1426/, GeneReviews: Bender et al., 2014, http://www.ncbi.nlm.nih.gov/books/NBK1377/). Therefore, this collective evidence supports the classification of the c.364G>C (p.Glu122Gln) as a Pathogenic variant for Beta Thalassemia.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506320 SCV000601298 uncertain significance not specified 2017-04-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506320 SCV000603898 pathogenic not specified 2018-07-19 criteria provided, single submitter clinical testing The Hb D-Los Angeles variant (HBB: c.364G>C; p.Glu122Gln, also known as Glu121Gln when numbered from the mature protein) is not associated with clinical symptoms in heterozygous carriers (HbVar database). Individuals homozygous for Hb D-Los Angeles are also commonly clinically asymptomatic (HbVar database, Torres 2015). Individuals with Hb D-Los Angeles who carry an additional pathogenic variant in their other copy of the beta globin gene may have clinically significant symptoms. Hb D-Los Angeles paired with Hb S has a wide phenotypic spectrum ranging from mild to severe sickle cell disease (Perea 1999, Torres 2015 and 2016). The clinical presentation in individuals with Hb D-Los Angeles and a beta-thalassemia variant is variable and influenced by the severity of the thalassemia variant, but is commonly characterized by mild to moderate hemolytic anemia (Perea 1999, Theodoridou 2009, Torres 2015 and 2016). REFERENCES Link to HbVar database for Hb D-Los Angeles: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=509&.cgifields=histD Perea F et al. Hb D-Los Angeles associated with Hb S or beta-thalassemia in four Mexican Mestizo families. Hemoglobin. 1999; 23(3):231-7. Theodoridou S et al. Compound heterozygosity for Hb D-Punjab / beta-thalassemia and blood donation: case report. Turk J Haematol. 2009 Jun 5;26(2):100-1. Torres LS et al. Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis. Rev Bras Hematol Hemoter. 2015 Mar-Apr;37(2):120-6. Torres LS et al. Phenotypic Diversity of Sickle Cell Disease in Patients with a Double Heterozygosity for Hb S and Hb D-Punjab. Hemoglobin. 2016 Sep;40(5):356-358.
Illumina Clinical Services Laboratory,Illumina RCV000778329 SCV000914516 likely pathogenic HBB-Related Disorders 2019-01-12 criteria provided, single submitter clinical testing The HBB c.364G>C (p.Glu122Gln) missense variant, which is also reported as p.Glu121Gln, Hb D-Punjab, and Hb D-Los Angeles, is the fourth most common haemoglobin variant found worldwide. Individuals who carry this variant in a heterozygous or homozygous state are generally asymptomatic, however, inheritance in a homozygous can result in a mild to moderate hemolytic anemia (Taghavi Basmanj et al. 2011; Torres et al. 2015). The p.Glu122Gln variant can occur in association with other hemoglobin variants, for example, HbS or thalassemia, resulting in moderate to severe clinical manifestations resembling a sickle cell disease phenotype or a mild microcytic and hypochromic anemia respectively (Adekile et al. 2010; Bender et al. 2014; Torres et al. 2015). The variant is reported at a frequency of 0.004997 in the South Asian population of the Genome Aggregation Database. Based on the evidence the p.Glu122Gln variant is classified as likely pathogenic for HBB-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000723826 SCV000957842 pathogenic not provided 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 122 of the HBB protein (p.Glu122Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs33946267, ExAC 0.4%). When observed in the heterozygous or homozygous state, this variant is generally asymptomatic, however, when co-inherited with HBB p.Glu7Val (also known as p.Glu6Val and HbS), this variant results in an HbSD phenotype, which is a moderate to severe phenotype similar to that seen in sickle cell anemia (PMID: 25666204, 24616059, 24245819). This variant is also known as p.Glu121Gln, HbD-Los Angeles, HbD-Punjab, HbD-North-Carolina, HbD-Portugal, and HbD-Chicago in the literature. ClinVar contains an entry for this variant (Variation ID: 15152). Experimental studies have shown that this missense change facilitates the polymerization of HbS (PMID: 2895770). In summary, this variant is generally asymptomatic in the heterozygous or homozygous state, but is clinically relevant when seen in compound heterozygosity with HBB p.Glu7Val (HbS). Therefore, this variant has been classified as Pathogenic.
Baylor Genetics RCV000202465 SCV001163643 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000029994 SCV001193798 likely pathogenic beta Thalassemia 2019-10-18 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.364G>C(E122Q, aka Hb D-Punjab) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy. Sources cited for classification include the following: PMID 5672850, 3557998, 4078867 and 1177278. Classification of NM_000518.4(HBB):c.364G>C(E122Q, aka Hb D-Punjab) 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.
Illumina Clinical Services Laboratory,Illumina RCV001103965 SCV001260787 uncertain significance 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001107583 SCV001264746 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
OMIM RCV000016317 SCV000036585 other Hb D-Los Angeles 2017-12-12 no assertion criteria provided literature only
GeneReviews RCV000202465 SCV000190691 pathogenic Hb SS disease 2014-10-23 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000029994 SCV000678142 likely pathogenic beta Thalassemia 2016-07-19 no assertion criteria provided clinical testing

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