ClinVar Genomic variation as it relates to human health

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

The HBB c.208G>A (p.Gly70Ser) variant (also known as Hb City of Hope) has been reported as having normal stability, with normal clinical presentation in heterozygotes (PMID: 6434492 (1984)). However, compound heterozygous individuals carrying this variant and a severe beta-thalassemia variant on the other allele may present with a beta-thalassemia intermedia phenotype (PMIDs: 25113778 (2015), 2467892 (1989)). The frequency of this variant in the general population, 0.018 (184/10366 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 70 of the HBB protein (p.Gly70Ser). This variant is present in population databases (rs33947415, gnomAD 1.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive mild to moderate beta thalassemia phenotypes and/or severe anemia and immunodeficiency (PMID: 2200760, 2467892, 25113778). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Gly69Ser, G69S, Hb City of Hope, and Hb CH. ClinVar contains an entry for this variant (Variation ID: 15138). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The Hb City of Hope variant (HBB: c.208G>A; p.Gly70Ser, also known as Gly69Ser when numbered from the mature protein; rs33947415, HbVar ID: 377) is reported in the literature in the heterozygous state in asymptomatic individuals (HbVar and references therein), and in trans to a pathogenic variant in an individual presenting with classical beta-thalassemia trait; however, this individual also carried an alpha-thalassemia deletion (--SEA), which could reduce the globin chain imbalance and minimize the clinical impact (Zhou 2019). Hb City of Hope has also been observed in trans to pathogenic HBB variants in several individuals with thalassemia intermedia or moderate to severe anemia (Paridisi 2010, Vinciguerra 2015). This variant is reported in ClinVar (Variation ID: 15138). It is found in the Ashkenazi Jewish population with an overall allele frequency of 1.8% (184/10366 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.584). Due to conflicting information, the clinical significance of the Hb City of Hope variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Paradisi I et al. Hemoglobin S/hemoglobin City of Hope compound heterozygote with a SubSaharan genetic background and severe bone marrow hypoplasia. Invest Clin. 2010 Sep;51(3):403-14. PMID: 21302591. Vinciguerra M et al. Co-inheritance of the rare B hemoglobin variants Hb Yaounde, Hb Gorwihl and Hb City of Hope with other alterations in globin genes: impact in genetic counseling. Eur J Haematol. 2015 Apr;94(4):322-9. PMID: 25113778. Zhou JY et al. Coinheritance of Hb City of Hope (HBB: c.208G>A) and B-Thalassemia: Compromising the Molecular Diagnosis of the Codons 71/72 (+A) (HBB: c.216_217insA) Mutation by Reverse Dot-Blot Hybridization. Hemoglobin. 2019 Mar;43(2):145-147. PMID: 31268351.

Variant summary: HBB c.208G>A (p.Gly70Ser) 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 0.00049 in 1614010 control chromosomes in the gnomAD v4.0.0 database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Hemoglobinopathy (0.00049 vs 0.011), allowing no conclusion about variant significance. This variant (also known as Hb City of Hope or Hb CH; also referred to as Gly69Ser) has been reported in several heterozygous carriers, who were found to be clinically and hematologically unaffected (e.g., Rahbar_1984, Wilson_1986). However, compound heterozygosity with a beta0-thallassemia allele has been reported in two independent patients, who had beta thalassemia intermedia phenotypes (e.g., Kutlar_1989, Oner_1990, Vinciguerra_2015). In addition, compound heterozygosity with HbS (HBB c.20A>T) was reported in an anemic 2-year-old boy (Paradisi_2010). In a recent study, the variant was reported in compound heterozygosity with a beta0-thalassemia allele in a clinically asymptomatic individual, who had classical beta-thalassemia trait based on hematological parameters, but no evidence of anemia, however this patient also carried an alpha-thalassemia deletion (--SEA), which could reduce the globin chain imbalance, thus modifying the clinical phenotype (Zhou_2019). These data, combined with the homozygous occurrences in the gnomAD database, suggest that the variant may cause disease when in trans with a null allele, and thus, the pathogenicity of the variant may be genotype-dependent. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1353069, 17932132, 2467892, 26436569, 2200760, 21302591, 6434492, 34092029, 31553106, 25113778, 3957690, 31268351). ClinVar contains an entry for this variant (Variation ID: 15138). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Heterozygous carriers have not been observed to have any hematologic manifestations (PMID: 21302591, 1353069); Also known as Hb City of Hope (HbCH) and G69S using alternate nomenclature; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31553106, 34297361, 28802248, 27823958, 31268351, 25113778, 21302591, 1353069, 6434492, 2467892, 34426522, 37028505, 37265972, Karaer2023[CaseReport])

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.