ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.67G>C (p.Glu23Gln) (rs33959855)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000589411 SCV000603917 likely benign not provided 2017-07-19 criteria provided, single submitter clinical testing The Hb D-Iran variant (c.67G>C, Glu22Gln) (rs33959855) has been reported in individuals with no associated hematological symptoms (Rehbar 1973, HbVar database and references therein), and did not affect clinical symptoms when occurring in-trans with beta-0 thalassemia alleles (Rohe 1973, Agrawal 2007). Functional characterizations indicate that the variant hemoglobin exhibits normal oxygen affinity, Bohr effect and cooperative interactions (Rohe 1973). The variant is listed in the ClinVar (Variation ID: 15151), and observed in the South Asian population of the Genome Aggregation Database general population database at a frequency of 0.05 percent (15/30780 alleles). The glutamine at residue 22 is highly conserved, but computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2) predict that the variant has no impact on the protein. Based on the above information, the variant is considered likely benign. References: Link to HbVar database for Hb D-Iran: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=267 Agrawal M et al. (2007) Compound heterozygosity of Hb D(Iran) (beta(22) Glu-->Gln) and beta(0)-thalassemia (619 bp-deletion) in India. Eur J Haematol. 79(3):248-50. Rehbar S (1973) Haemoglobin D Iran: 2 22 glutamic acid leads to glutamine (B4). Br J Haematol. 24(1):31-5. Rohe R et al. (1973) Hemoglobin D Iran alpha A2 beta 22 2-Glu leads to Gln in association with thalassemia. Blood. 42(3):455-62.
Integrated Genetics/Laboratory Corporation of America RCV000589411 SCV000697142 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The HBB c.67G>C (p.Glu23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant is present in the control population dataset of ExAC at a frequency of 0.00005 (7/121364 chrs tested), exclusively in individuals of South Asian descent 0.0004239 (7/16512 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant in this gene (0.011). Hb D-Iran was identified in compound heterozygosity with HbA with an asymptomatic clinical course, normal hemoglobin concentration, normal red blood cell morphology, absence of inclusion bodies, and a normal level of methemoglobin (Rahbar, 1973). Hb D-Iran in combination with HbS causes benign sickle syndrome with normal red cell indices, normal growth, and no evidence of hemolysis or organomegaly (Serjeant, 1982). A compound heterozygotes for Hb D-Iran and - thal presented with hypochromic microcytic anemia with target cells and basophilic stippling with these finding being no different from those of a - thal carriers alone (Rohe, 1973; Agrawal, 2007; Bhat, 2012). Thornburg (2001) concluded that homozygous Hb D-Iran is a relatively benign condition with mild microcytic anemia, poikilocytosis, and minimal hemolysis based on the hematologic values, hemoglobin electrophoresis, peripheral blood smear, and clinical course. Hb D-Iran has no reported abnormalities in heat stability, oxygen equilibrium, intracellular 2,3 DPG, Bohr effect, or hemeheme interactions (Rohe, 1973). Additional reports of presence in controls and in patients with alternate molecular basis of disease would be required to classify this variant as benign or likely benign. Considering all, the variant was classified as VUS-Possibly Benign to emphasize the need for additional genotype-clinical phenotype correlations and that although the variant does not alter remarkably the clinical manifestations due to a known pathogenic variant in trans, the presence of some relatively mild clinical manifestations cannot be ruled out.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589411 SCV000889377 likely benign not provided 2018-02-18 criteria provided, single submitter clinical testing
OMIM RCV000016314 SCV000036582 other HEMOGLOBIN D (IRAN) 2017-12-12 no assertion criteria provided literature only

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