Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000589411 | SCV000603917 | likely benign | not provided | 2022-05-13 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001280542 | SCV000697142 | uncertain significance | not specified | 2023-10-31 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.67G>C (p.Glu23Gln) results in a conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251278 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia (6e-05 vs 0.011), allowing no conclusion about variant significance. Hb D-Iran was identified in compound heterozygosity with Hb A 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 heterozygote 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, Mohanty_2017). 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 heme-heme interaction (Rohe_1973). The following publications have been ascertained in the context of this evaluation (PMID: 35287566, 17655708, 19783722, 23543793, 27207683, 8195010, 25332633, 9342003, 29519374, 33279152, 4715135, 4725603, 20090224, 20838957, 31553106, 7073867, 11196276, 20309827). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=2) or VUS (n=1). 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. Based on the evidence outlined above, 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 remarkably alter 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 | 2023-04-26 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000589411 | SCV002558068 | uncertain significance | not provided | 2022-07-21 | criteria provided, single submitter | clinical testing | Reported in the homozygous and compound heterozygous state in patients with mild hemoglobinopathy (Thornburg et al., 2001; Bhat et al., 2012; Gupta et al., 2014); Also known as Hb D-Iran and p.E22Q; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20090224, 4715135, 8195010, 6434492, 7073867, 25023086, 20838957, 19783722, 4725603, 11196276, 17655708, 31553106, 20309827, 23543793, 25332633, 19429541) |
| OMIM | RCV000016314 | SCV000036582 | other | HEMOGLOBIN D (IRAN) | 2017-12-12 | no assertion criteria provided | literature only |