ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.238G>C (p.Asp80His) (rs33990858)

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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 RCV001001454 SCV001158701 uncertain significance not specified 2019-04-10 criteria provided, single submitter clinical testing The Hb Tigraye (HBB: c.238G>C; p.Asp80His, also known as Asp79His when numbered from the mature protein; rs33990858) is reported in the literature in several healthy individuals with normal hematology (Pistidda 2001, HbVar and references therein). This variant is reported in ClinVar (Variation ID: 15522), but it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at codon 80 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, though these are low-confidence predictions. Additionally, other amino acid substitutions at this codon (Asn, Tyr, Gly, and Ala) have been reported in clinically normal individuals, including a healthy individual homozygous for the p.Asp80Tyr variant (Lehmann 1964, HbVar database), and are not reported in association with disease, suggesting missense variants at this codon may be tolerated. However, studies in separate families by two groups measured increased oxygen affinity in Hb Tigraye (Pistidda 2001; Molchanova 1993). Although erythrocyte indices were normal in carriers, it is uncertain what the effect would be in combination with a beta-thalassemia variant. Given the lack of clinical and functional data, the significance of the p.Asp80His variant is uncertain at this time. References: HbVar link to Hb Tigraye: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=400 Lehmann H et al. Haemoglobin GACCRA. Nature. 1964; 203:363-5. Molchanova TP et al. Hb Tigraye or alpha 2 beta (2)79(EF3)Asp-->His(GAC-->CAC): a hemoglobin variant with increased oxygen affinity observed in an Ethiopian male. Hemoglobin. 1993 Jun;17(3):247-50. Pistidda P et al. Hb Tigraye [beta79(EF3)Asp --> His] in a Caucasian family from Sardinia. Hemoglobin. 2001 Aug;25(3):341-5.
OMIM RCV000016786 SCV000037056 other HEMOGLOBIN TIGRAYE 2017-12-12 no assertion criteria provided literature only

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