ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.208G>A (p.Gly70Ser) (rs33947415)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000587680 SCV000333005 likely pathogenic not provided 2015-08-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855646 SCV000697092 uncertain significance not specified 2021-07-06 criteria provided, single submitter clinical testing 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 0.00094 in 251422 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00094 vs 0.011), allowing no conclusion about variant significance. This variant (aka Hb City of Hope or Hb CH; also referred to as Gly69Ser) was reported in several heterozygous carriers, who were found to be clinically and hematologically unaffected. However, compound heterozygosity with a beta0-thallassemia allele has been reported in two independent patients, who had beta thalassemia intermedia phenotypes (Kutlar_1989, Oner_1990, Vinciguerra_2015). In addition, compound heterozygosity with Hb S (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 indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance/other and two ClinVar submitters (evaluation after 2014) cite it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000587680 SCV000941382 likely pathogenic not provided 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 70 of the HBB protein (p.Gly70Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs33947415, ExAC 0.1%). This variant has been observed in the heterozygous state in individuals and families who were clinically unaffected and without hematological manifestations (PMID: 1353069, 6434492, 26436569). However, individuals that carried this variant in trans with another known disease-causing HBB variant displayed mild to moderate beta thalassemia phenotypes (PMID: 25113778, 2467892, 2200760) or severe anemia and immunodeficiency (PMID: 21302591), suggesting that it may not be a clinically silent variant. This variant is also known as p.Gly69Ser, G69S, Hb City of Hope, and Hb CH in the literature. ClinVar contains an entry for this variant (Variation ID: 15138). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Baylor Genetics RCV001004567 SCV001163651 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000396079 SCV001264147 uncertain significance beta Thalassemia 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001107022 SCV001264148 uncertain significance Hemoglobin E 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001107023 SCV001264149 uncertain significance Fetal hemoglobin quantitative trait locus 1 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV001004567 SCV001264150 uncertain significance Hb SS disease 2017-04-27 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587680 SCV001470522 uncertain significance not provided 2019-11-22 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV001004567 SCV001653380 uncertain significance Hb SS disease 2021-05-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV001535933 SCV001752591 likely pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis 6, familial 2021-06-30 criteria provided, single submitter clinical testing
OMIM RCV000016301 SCV000036569 other HEMOGLOBIN CITY OF HOPE 2017-12-12 no assertion criteria provided literature only
Bodamer Research Lab,Boston Children's Hospital RCV000396079 SCV000599992 uncertain significance beta Thalassemia 2016-02-24 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000709890 SCV000840231 not provided Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Hb SS disease; beta Thalassemia no assertion provided phenotyping only 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.

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