ClinVar Miner

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

dbSNP: rs33946267
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Eurofins Ntd Llc (ga) 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 RCV000723826 SCV000601298 likely pathogenic not provided 2023-01-09 criteria provided, single submitter clinical testing In the published literature, individuals who are heterozygous or homozygous for this variant typically have a normal clinical presentation (PMIDs: 30626242 (2018), 25666204 (2015), 24123366 (2014), 12403491 (2002), and 1177278 (1975)). There have been individuals reported to have mild anemia when compound heterozygous with additional HBB variants (PMIDs: 31973650 (2020), 9140717 (1997), and 4078867 (1985)). However, individuals who are compound heterozygous for the Hb D-Los Angeles and Hb S variants have a clinically significant sickling disorder that is similar to sickle cell disease (PMIDs: 25818823 (2015), 24616059 (2014), and 5672850 (1968)). Additionally, individuals who are compound heterozygous for the Hb D-Los Angeles variant and a beta-globin pathogenic variant associated with beta-thalassemia may be affected by beta-thalassemia (PMID: 30626242 (2018), 25087612 (2014), 22028795 (2011), 2307460 (1990)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, this variant is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000723826 SCV000603898 pathogenic not provided 2023-11-21 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, HbVar ID: 509) 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 HbS has a wide phenotypic spectrum ranging from mild to severe sickle cell disease (Perea 1999, Torres 2015 and 2016). Functional studies found an increased rate of nucleation and polymerization in Hb S- D Los Angeles samples as compared with Hb S (Adachi 1988). 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). This variant is reported in ClinVar (Variation ID: 15152) and is found in the South Asian population with an allele frequency of 0.5% (153/30616 alleles, including 4 homozygotes) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Adachi K et al. Facilitation of Hb S polymerization by the substitution of Glu for Gln at beta 121. J Biol Chem. 1988 Apr 25;263(12):5607-10. PMID: 2895770. 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. PMID: 10490135. 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. PMID: 27265282. Torres LS et al. Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis. Rev Bras Hematol Hemoter. 2015 Mar-Apr;37(2):120-6. PMID: 25818823. 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. PMID: 27535451.
Illumina Laboratory Services, Illumina RCV000778329 SCV000914516 likely pathogenic HBB-related disorder 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000723826 SCV000957842 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 122 of the HBB protein (p.Glu122Gln). This variant is present in population databases (rs33946267, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with an HbSD phenotype, which occurs when this variant is co-inherited with HBB p.Glu7Val (also known as p.Glu6Val and HbS). HbSD is a moderate to severe phenotype similar to that seen in sickle cell anemia. When observed in the heterozygous or homozygous state, this variant is generally asymptomatic. (PMID: 24245819, 24616059, 25666204). This variant is also known as p.Glu121Gln, HbD-Los Angeles, HbD-Punjab, HbD-North-Carolina, HbD-Portugal, and HbD-Chicago. ClinVar contains an entry for this variant (Variation ID: 15152). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. Experimental studies have shown that this missense change affects HBB function (PMID: 2895770). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000202465 SCV001163643 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Genetics, 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.‚Äã
Clinical Genetics and Genomics, Karolinska University Hospital RCV000723826 SCV001449712 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000202465 SCV001716384 likely pathogenic Hb SS disease 2021-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000723826 SCV001770636 pathogenic not provided 2022-07-23 criteria provided, single submitter clinical testing Considered a founder mutation with prevalence in the Punjabi region of India, Italy, Belgium, Austria, and Turkey (Torres Lde et al., 2015); Also referred to as E121Q due to the use of alternative nomenclature, and commonly called HbD Punjab or HbD Los Angeles (Torres Lde S et al., 2015); Published functional studies suggest a damaging effect, including decreased oxygen affinity of HbD (Narayanan et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 3557998, 25087612, 22975760, 19958184, 25666204, 24123366, 22028795, 2307460, 26680249, 26990548, 8095930, 12403491, 24616059, 2895770, 20110664, 5672850, 4078867, 21194265, 25818823, 24814631, 28970692, 9140717, 30626242, 31553106, 31973650, 31980526, 34426522, 33867742, 6592161, 10490135, 32468185, 1177278)
Mendelics RCV002247348 SCV002516535 pathogenic Heinz body anemia 2022-05-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000029994 SCV004847541 pathogenic beta Thalassemia 2022-11-03 criteria provided, single submitter clinical testing The p.Glu122Gln variant in HBB (also known as Glu121Gln, HbD-Los Angeles, HbD-Punjab, HbD-North-Carolina, HbD-Portugal, and HbD-Chicago) is considered a founder mutation in the Punjabi region of India, Italy, Belgium, Austria, and Turkey (Torres Lde 2015 PMID: 25818823). Heterozygous carriers, but also homozygous individuals, are commonly clinically asymptomatic (HbVar database, Torres Lde 2015 PMID: 25818823). However, individuals who carry this variant in trans with another pathogenic variant may have clinically significant symptoms e.g., sickle cell disease or hemolytic anemia (Perea 1999 PMID: 10490135, Theodoridou 2009 PMID: 27265282, Torres Lde 2015 PMID: 25818823). This variant has also been reported in ClinVar (Variation ID 15152). It has been identified in 21/4828 South Asian and in 10/68032 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies support an impact on protein function (Adachi 1988 PMID: 2895770). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hemoglobinopathy. ACMG/AMP Criteria applied: PM3_VS, PS3_Moderate.
OMIM RCV000016317 SCV000036585 other Hb D-Los Angeles 2017-12-12 no assertion criteria provided literature only
GeneReviews RCV000202465 SCV000190691 not provided Hb SS disease no assertion provided literature only
Natera, Inc. RCV000029994 SCV002089185 pathogenic beta Thalassemia 2017-03-17 no assertion criteria provided clinical testing

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