ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.23A>G (p.Glu8Gly) (rs34387455)

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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 RCV000781437 SCV000883985 likely benign not specified 2018-09-04 criteria provided, single submitter clinical testing The Hb G-San Jose variant (HBB c.23A>G; p.Glu8Gly, also known as Glu7Gly when numbered from the mature protein, rs34387455), is not associated with any clinically significant symptoms in individuals who are homozygous carriers of the variant, or compound heterozygous with a pathogenic HBB variant (Lacerra 2002, Musumeci 1979, HbVar link). This variant has been reported to have normal Bohr effect, cooperativity, and oxygen affinity, but is slightly unstable at elevated temperatures (Roth 1977). This variant is reported in ClinVar (Variation ID: 15176), and is found in the general population with an overall allele frequency of 0.001% (3/245,938 alleles) in the Genome Aggregation Database. The glutamate at codon 8 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to the absence of associated clinical symptoms, the Hb G-San Jose variant is considered to be likely benign. REFERENCES Link to HbVar database for Hb G-San Jose: Lacerra G et al. Hb G-San Jose variant levels correlate with alpha-thalassemia genotypes. Hemoglobin. 2002 Feb;26(1):59-66. Musumeci S et al. Hemoglobin G San Jose (beta 2 7 (A4) Glu to Gly alpha 2), beta thalassemia, and alpha thalassemia in a Sicilian family. Hum Genet. 1979 Nov;52(2):239-47. Roth EF Jr et al. Some properties of Hb G San Jose (beta7 glu replaced by gly): comparisons with Hb S. J Lab Clin Med. 1977 Nov;90(5):837-43.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000756237 SCV000889366 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781437 SCV000919457 likely benign not specified 2018-04-24 criteria provided, single submitter clinical testing Variant summary: HBB c.23A>G (p.Glu8Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245938 control chromosomes (in gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (1.2e-05 vs 0.011), allowing no conclusion about variant significance. The variant, c.23A>G has been reported in the literature in a healthy individual in homozygosity (Brancati_1989) as well as in several healthy carriers (e.g. Smith_2016). The variant is known in the literature as a rare polymorphism that has been reported mostly in Southern Italian or of Mexican families (Lacerra 2002). Individuals, who have the variant of interest together with b-thal mutation are likely to have hematological values reflecting their b-thal carrier status. Studies of functional properties confirmed that the variant protein has normal oxygen affinity, cooperativity and Bohr effect with a slightly decreased stability that may have only a marginal role, considering that the variant is not associated with a clinically significant hemolytic process (Roth_1977, Lacerra_2002). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as Likely Benign.
OMIM RCV000016353 SCV000036621 other HEMOGLOBIN G (SAN JOSE) 2017-12-12 no assertion criteria provided literature only

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