ClinVar Miner

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

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Total submissions: 7
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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
Integrated Genetics/Laboratory Corporation of America RCV000855646 SCV000697092 uncertain significance not specified 2019-04-08 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 0.00088 in 277114 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00088 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 heterozygous carriers (in at least nine individuals from six families), who were found to be clinically and hematologically unaffected. However, three studies suggest that Gly69Ser mutation should not be considered as a clinically/functionally silent variant when found in compound heterozygosity with other known abnormal globin gene variants, because those individuals presented with a mild to severe anemic phenotype (Kutlar 1989, Paradisi 2010, Vinciguerra 2015), consistent with a recessive mode of inheritance. 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. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, while the other laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000587680 SCV000941382 likely pathogenic not provided 2018-12-19 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.
OMIM RCV000016301 SCV000036569 other HEMOGLOBIN CITY OF HOPE 2017-12-12 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000029969 SCV000052624 uncertain significance Beta thalassemia intermedia 2015-10-02 no assertion criteria provided clinical testing
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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