ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.437A>G (p.Tyr146Cys) (rs35117167)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284491 SCV001470318 pathogenic not provided 2019-11-11 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Conflicting predictions of the effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287757 SCV001474477 pathogenic none provided 2020-04-21 criteria provided, single submitter clinical testing The Hb Rainier variant (HBB: c.437A>G; p.Tyr146Cys, also known as Tyr145Cys when numbered from the mature protein, rs35117167) is reported in the literature in the heterozygous state in multiple individuals affected with erythrocytosis (see link to HbVar and references therein, Adamson 1969). This variant is reported in ClinVar (Variation ID: 15322), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 146 is highly conserved, and functional analyses of the variant protein show increased oxygen affinity (see link to HbVar, Adamson 1969). Additionally, other amino acid substitutions at this codon (Hb Nancy, Hb Osler, Hb Bethesda, Hb McKees Rocks) have been reported in individuals with erythrocytosis and are considered pathogenic (HbVar IDs: 570, 572, 573, 574), and several hemoglobin variants with high oxygen affinity leading to erythrocytosis are located at the carboxy-terminal end of the HBB gene (Wajcman 2004). Based on available information, the Hb Rainier variant is considered to be pathogenic. References: Link to HbVar for Hb Rainier: Adamson JW et al. Erythrocytosis associated with hemoglobin Rainier: oxygen equilibria and marrow regulation. J Clin Invest. 1969 Aug;48(8):1376-86. Wajcman H and Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106.
OMIM RCV000016562 SCV000036830 other HEMOGLOBIN RAINIER 2017-12-12 no assertion criteria provided literature only
OMIM RCV000641598 SCV000763240 pathogenic Erythrocytosis 6, familial 1999-05-01 no assertion criteria provided literature only

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