Submissions for variant NM_000518.5(HBB):c.50G>A (p.Gly17Asp)

gnomAD frequency: 0.00003  dbSNP: rs33962676

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755547	SCV000603935	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755547	SCV000889373	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	The HBB c.50G>A (p.Gly17Asp, also known as Hb J-Baltimore) variant is described in heterozygous individuals as having a normal clinical presentation. In the published literature, individuals heterozygous for Hb J-Baltimore and Hb S or Hb C have been described as having clinical and hematological findings similar to carriers of Hb S and Hb C alone (PMID: 14117783 (1963)). 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, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004562214	SCV000917499	uncertain significance	not specified	2023-11-14	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). 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). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1) ans VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	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, Revvity	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