Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000755547 | SCV000603935 | benign | not provided | 2024-10-30 | criteria provided, single submitter | clinical testing | The Hb J-Baltimore variant (HBB: c.50G>A; p.Gly17Asp, also known as Gly16Asp when numbered from the mature protein, rs33962676, HbVar ID: 247) is a stable hemoglobin variant that has been described in a patient with sickle hemoglobin, who is clinically asymptomatic and exhibits mild but well-compensated hemolytic anemia (Went 1959). It has also been reported with beta-thalassemia variants, and either has no impact or ameliorates the associated clinical symptoms (Ballas 1981, Wong 1971). The Hb J-Baltimore variant is found in the general population with an overall allele frequency of 0.002% (7/282640 alleles) in the Genome Aggregation Database The glycine at codon 17 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.575). The Hb J-Baltimore variant is considered to be benign as it has not been reported to be associated with a significant clinical phenotype (see HbVar link and references therein). REFERENCES Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Ballas SK et al. Globin chain synthesis in Hb J Baltimore-beta (+)-thalassemia. Am J Clin Pathol. 1981; 75(6):843-6. PMID: 6167160 Went L et al. Sickle-Cell/Haemoglobin-J Disease. Br Med J. 1959; 2(5144): 138-139. PMID: 13843994 Wong S et al. Hb-J-Georgia=Hb-J-Baltimore= alpha2 beta2 16 Gly leads to Asp. Clin Chim Acta. 1971; 35(2):521-2. PMID: 5125343 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000755547 | SCV000889373 | uncertain significance | not provided | 2024-11-05 | criteria provided, single submitter | clinical testing | The HBB c.50G>A (p.Gly17Asp) variant (also known as Hb J-Baltimore) has been reported in the heterozygous state in individuals with normal clinical presentation (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), and PMIDs: 26901597 (2015), 8745435 (1996), 8226093 (1993), 14117783 (1964)). Individuals who carry Hb J-Baltimore in combination with the Hb S (HBB c.20A>T, p.Glu7Val) or Hb C (HBB c.19G>A, p.Glu7Lys) pathogenic variant have clinical and hematological findings similar to carriers of Hb S or Hb C alone (PMID: 14117783 (1964)). Hb J-Baltimore is also reported to have normal stability (PMIDs: 8226093 (1993), 8745435 (1996)). The frequency of this variant in the general population, 0.000054 (7/129002 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004562214 | SCV000917499 | uncertain significance | not specified | 2024-12-05 | criteria provided, single submitter | clinical testing | Variant summary: HBB c.50G>A (p.Gly17Asp) results in a non-conservative amino acid change in 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 4.9e-05 in 1613680 control chromosomes (gnomAD database v4). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Hemoglobinopathy (4.9e-05 vs 0.011), allowing no conclusion about variant significance. The variant, c.50G>A, has been reported in the literature in multiple compound heterozygotes carrying the variant of interest and HbS (e.g. Weatherall_1964, Baglioni_1963, Huisman_1978), and at least 3 of these individuals has been stated to have no symptoms suggestive of anemia or sickle-cell crisis during several years of follow up (Weatherall_1964). A functional study, which measured the rate of change of blood viscosity during deoxygenation demonstrated that blood from a compound heterozygote, behaved similarly to that of sickle-cell carriers, i.e. the variant didn't contribute to sickling (Weatherall_1964, Charache_1964). The variant also has been reported in at least 3 compound heterozygotes who carried a beta-thalassemia allele (Musumeci_1979, Arribalzaga_1996), these individuals had hematological parameters largely similar to individuals with beta-thalassemia trait. Functional studies performed on samples from two of these individuals, indicated normal oxyhemoglobin dissociation curves and P50 values, similar to thalassemia carriers (Arribalzaga_1996). Other functional studies noted no Heinz-body formation, or instability, in addition, oxygen affinity, Bohr-effect, and cooperativity, were all noted to be similar to normal (e.g. Musumeci_1979, Arribalzaga_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8745435, 14092068, 14194270, 20206586, 19429541, 6859036, 700140, 16178917, 19750260, 5481775, 14282052, 3957922, 511585, 31553106, 17709689, 14117783). ClinVar contains an entry for this variant (Variation ID: 15213). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
| Gene |
RCV000755547 | SCV002552711 | uncertain significance | not provided | 2022-01-21 | criteria provided, single submitter | clinical testing | Reported in combination with either hemoblobin S, hemoglobin C, or beta thalassemia trait, but limited clinical information is provided on these individuals (Baglioni and Weatherall, 1963; Huisman et al., 1978; Musumeci et al., 1979; Arribalzaga et al., 1996); Observed in the heterozygous state in a mother and daughter with abnormally low HbA1c levels (Gargallo et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also described as Gly16Asp or Hb J-Baltimore using alternate nomenclature (Baglioni and Weatherall, 1963; Gargallo et al., 2010; Riou et al., 2015); This variant is associated with the following publications: (PMID: 27535164, 3808941, 14117783, 8226093, 5125343, 19429541, 31553106, 14092068, 511585, 24200101, 8745435, 19750260, 20206586, 25130136, 700140) |
| Revvity Omics, |
RCV000755547 | SCV004235260 | uncertain significance | not provided | 2023-07-17 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000016400 | SCV000036668 | other | HEMOGLOBIN J (BALTIMORE) | 1979-01-01 | no assertion criteria provided | literature only |