ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.286A>G (p.Lys96Glu) (rs33914359)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755549 SCV000601266 likely benign not provided 2019-06-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282808 SCV000603949 likely benign none provided 2020-07-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000506157 SCV000917491 likely benign not specified 2019-01-22 criteria provided, single submitter clinical testing Variant summary: HBB c.286A>G (p.Lys96Glu) also known as Hb-N Baltimore, results in a conservative amino acid change located in the Globin domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277156 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Multiple publications cite the variant with in asymptomatic and mildly affected individuals with normal hematological parameters characteristic of alpha thal-trait (in settings of -alpha/-alpha genotype) or a beta-thal trait (in setting of Hb-N-Baltimore/beta-thal) (Johnson_1976, Adams_1977, Ballas_1985, Hirsch_1997, Huisman_1997). A case study by Farashi_2016 reports the variant to occur in cis with HBB c.272_295dup (a duplication of eight codons) in a mother and daughter with relatively normal hematological parameters, however, authors speculate that the variant of interest could also influence structural changes. Functional studies showed that this variant significantly accelerated the crystallization of HbC (Hirsch_1997), inhibited gelation of HbS in deoxy state while behaving like HbA in oxy state (Kumpati_1978) and was associated with normal oxygen affinity (Craescu_1988). Furthermore, the variant showed poor reducibility of oxidized hemoglobin and impairment in interaction with cytochrome b5 (Gacon_1980). However, the impact of these findings on the pathophysiology of hemoglobinopathies is unclear. This variant is widely regarded as an apparently harmless or a clinically benign hemoglobin in the literature spanning over 3 decades (example, Schneider_1976, Mason_2016). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000016504 SCV000036772 other HEMOGLOBIN N (BALTIMORE) 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016505 SCV000036773 other HEMOGLOBIN N (JENKINS) 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016506 SCV000036774 other HEMOGLOBIN JENKINS 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016507 SCV000036775 other HEMOGLOBIN HOPKINS 1 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016508 SCV000036776 other HEMOGLOBIN KENWOOD 2017-12-12 no assertion criteria provided literature only

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