ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.44T>C (p.Leu15Pro)

gnomAD frequency: 0.00001  dbSNP: rs33935445
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508682 SCV000605836 uncertain significance not provided 2024-08-23 criteria provided, single submitter clinical testing The HBB c.44T>C (p.Leu15Pro) variant (also known as Hb Saki) has been reported to be unstable, with normal clinical presentation in heterozygotes (PMID: 998617 (1976), and HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). The frequency of this variant in the general population, 0.0000066 (1/152206 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001527030 SCV001737852 uncertain significance not specified 2021-05-25 criteria provided, single submitter clinical testing Variant summary: HBB c.44T>C (p.Leu15Pro) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. This variant is also known in the literature as Hb-Saki. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251236 control chromosomes. c.44T>C has been reported in the literature in at least 2 families (e.g. Milner_1976, Beuzard_1975). At least 2 heterozygous individuals with the variant had no clinical symptoms reported, while a patient with the variant in compound heterozygosity with an unspecified mutation had a history of anemia, enlarged spleen, and an episode of severe hemolysis (e.g. Milner_1976). Evaluation of red cells from individuals with the variant showed mild instability (e.g. Milner_1976). Two other ClinVar submitters (evaluation after 2014) cited the variant as uncertain significance (n=1) and "other" (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508682 SCV002506312 uncertain significance not provided 2021-12-01 criteria provided, single submitter clinical testing The Hb Saki variant (HBB: c.44T>C; p.Leu15Pro, also known as Leu14Pro when numbered from the mature protein, rs33935445) is reported in the literature in multiple clinically healthy heterozygous individuals (see link to HbVar and references therein). This variant has also been reported in compound heterozygosity with an unspecified variant in an individual with beta-thalassemia intermedia (HbVar). This variant does not separate from Hb A during electrophoresis (see link to HbVar). This variant has also been reported along with Hb S in a clinically healthy individual (HbVar). This variant is reported as unstable, but with normal oxygen affinity, Bohr effect, and cooperativity (HbVar). This variant is reported in ClinVar (Variation ID: 15341) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 15 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.822). Due to limited information, the clinical significance of the p.Leu15Pro variant is uncertain at this time. References: Link to Hb Var database for Hb Saki: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=244&.cgifields=histD
Fulgent Genetics, Fulgent Genetics RCV002490377 SCV002801539 uncertain significance Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB 2022-04-23 criteria provided, single submitter clinical testing
OMIM RCV000016584 SCV000036853 other HEMOGLOBIN SAKI 2017-12-12 no assertion criteria provided literature only
Natera, Inc. RCV001826467 SCV002091607 uncertain significance beta Thalassemia 2019-02-21 no assertion criteria provided clinical testing

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