ClinVar Miner

Submissions for variant NM_000558.3(HBA1):c.341T>A (p.Leu114His) (rs35654345)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000509 SCV001157414 likely benign not specified 2019-01-17 criteria provided, single submitter clinical testing The HBA1 c.341T>A; p.Leu114His variant (Leu113His when numbered from the mature protein; rs35654345), commonly known as Hb Twin Peaks, is reported as a stable hemoglobin variant and is not associated with clinical symptoms in a heterozygous state (HbVar database and references therein). In vitro studies also demonstrate that this variant increases the solubility of Hb S when forming the globin tetramer, potentially acting as an inhibitor of polymerization (Sivaram 2001). This variant is listed in ClinVar (Variation ID: 15829), and is only observed on 5 alleles in the Genome Aggregation Database. The leucine at codon 113 is weakly conserved, and computational analyses (PolyPhen-2, SIFT) predict that this variant is tolerated. Based on available information, the Hb Twin Peaks variant is considered to be likely benign. References: Link to HbVar database for Hb Twin Peaks: Sivaram M et al. A role for the alpha 113 (GH1) amino acid residue in the polymerization of sickle hemoglobin. Evaluation of its inhibitory strength and interaction linkage with two fiber contact sites (alpha 16/23) located in the AB region of the alpha-chain. J Biol Chem. 2001; 276(21):18209-15.
OMIM RCV000017173 SCV000037445 other HEMOGLOBIN TWIN PEAKS 2016-07-20 no assertion criteria provided literature only

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