ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.98T>A (p.Leu33Gln) (rs33948578)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286647 SCV001473255 likely pathogenic none provided 2020-05-19 criteria provided, single submitter clinical testing The Hb Clermont Ferrand variant (HBB: c.98T>A; p.Leu33Gln, also known as Leu32Gln when numbered from the mature protein, rs33948578) is reported in an individual with mild hemolytic anemia (HbVar database). This variant has also been observed in cis to the Hb Koln variant (c.295G>A; p.Val99Met) in another individual with hemolytic anemia, a complex variant reported as Hb Medicine Lake (Coleman 1995). The p.Leu33Gln variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The leucine at codon 33 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Leu33Arg, p.Leu33Pro) have been reported de novo in individuals with hemolytic anemia, and are considered disease-causing, unstable variants (Chang 2002, Walker 2003). Based on available information, the p.Leu33Gln variant is considered to be likely pathogenic. References: Link to Hb Clermont Ferrand in HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2542 Chang JG et al. Unstable Hb Perth in a Taiwanese subject: a T-->C substitution at codon 32 of the beta-globin gene creates an MspI site. Hemoglobin. 2002 Feb;26(1):91-4. Coleman MB et al. Two missense mutations in the beta-globin gene can cause severe beta thalassemia. Hemoglobin Medicine Lake (beta 32[B14]leucine-->glutamine; 98 [FG5] valine-->methionine). J Clin Invest. 1995 Feb;95(2):503-9. Walker L et al. Hb Castilla [beta32(B14)Leu --> Arg] caused by a de novo mutation. Hemoglobin. 2003 Nov;27(4):253-6.

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