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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755549 SCV000603949 likely benign not provided 2017-08-14 criteria provided, single submitter clinical testing The Hb N-Baltimore variant (HBB: c.286A>G; Lys95Glu) (rs33914359) is reported in multiple individuals with no associated clinical symptoms (Clegg 1965, Gottlieb 1967), even when found with Hb C (HbVar database and references therein). The variant hemoglobin is stable, as it is detected in half of all hemoglobin in all carriers (Clegg 1965, Gottlieb 1967). However, it has been reported to accelerate crystallization of Hb C in vitro (Hirsch 1997), but physiological ratios were not tested. Hb N-Baltimore is reported in ClinVar (Variation ID: 15278), and found in the general population with an overall allele frequency of 0.001% (4/277156 alleles) in the Genome Aggregation Database. The lysine at residue 95 is highly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. However, due to the absence of associated clinical symptoms and the relative stability of the variant hemoglobin, Hb N-Baltimore is considered to be likely benign. REFERENCES Link to HbVar database for Hb N-Baltimore: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=439 Clegg J et al. An improved method for the characterization of human haemoglobin mutants: identification of alpha-2-beta-2-95GLU, haemoglobin N (Baltimore). Nature. 1965; 207(5000):945-7. Gottlieb A et al. Primary structure of Hopkins-1 haemoglobin. Nature. 1967; 214(5084):189-90. Hirsch RE et al. HbC compound heterozygotes [HbC/Hb Riyadh and HbC/Hb N-Baltimore] with opposing effects upon HbC crystallization. Br J Haematol. 1997 May;97(2):259-65.
Integrated Genetics/Laboratory Corporation of America RCV000506157 SCV000917491 uncertain significance not specified 2017-09-25 criteria provided, single submitter clinical testing Variant summary: The HBB c.286A>G (p.Lys96Glu) variant (also known as Hb N-Baltimore, Hb Hopkins-I, Hb Jenkins, Hb Kenwood, Hb N-Memphis, and Lys95Glu) involves the alteration of a conserved nucleotide located in the Globin-like (IPR009050) domain (InterPro) and 2/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome for this variant. Functional studies showed that this variant significantly accelerated the crystallization of HbC (Hirsch_1997), inhibited gelation in deoxy state while behaving like HbA in oxy state (Kumpati_1978), and was associated with normal oxygen affinity (Craescu_HBB_JBC_1988). The variant was found in the control population dataset of gnomAD in 4/277156 control chromosomes at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). Multiple publications cite the variant with conflicting classifications in affected, asymptomatic, and mildly affected individuals (Adams_1977, Ballas_1985, Hirsch_1997, Lorenzo-Medina_2014). Farashi_2016 reports the variant to occur in cis with a duplication, however, authors are uncertain whether the variant of interest could also influence structural changes. Considering the conflicting clinical and functional data, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506157 SCV000601266 likely benign not specified 2017-06-10 criteria provided, single submitter clinical testing

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