ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.389C>T (p.Ala130Val) (rs111645889)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260264 SCV000697128 uncertain significance not specified 2021-04-08 criteria provided, single submitter clinical testing Variant summary: HBB c.389C>T (p.Ala130Val, also known as Hb La Desirade) results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes. c.389C>T has been reported in the literature in compound heterozygosity with other hemoglobin variants (including HbS, HbC, Hb E, Hb Louisville (p.Phe42Leu) and beta-thal-0) in individuals affected with hemoglobinopathies (e.g. Merault_1986, Kleinert_2008, Hassan_2015, Henderson_2016, Kamseng_2017), but also unaffected individuals (e.g. Merault_1986, Kamseng_2017). Since the penetrance of Hemoglobinopathy (0.63 in cases where clinical and complete genetic information was available) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. Individuals carrying this variant in compound heterozygosity with other hemoglobin variants have been reported with mild phenotypes such as an elevated reticulocyte count or mild anemia. In a population study, the variant was found in 15 individuals affected by beta hemoglobinopathy in whom no additional HBB variants were detected, however no clinical information (severity of phenotypes and/or differential diagnosis) was provided (Hassan 2015). At least one publication reports experimental evidence indicating that the variant results in a mild decrease in oxygen affinity and precipitation during the isopropanol test, suggestive of an unstable hemoglobin (Merault 1986). A patient who was compound heterozygous for this variant and Hb Louisville was observed to have 10-20% inclusion bodies in blood cells on a blood smear (Kamseng_2017). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and cited the variant as likely benign (n=1), 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 RCV000589768 SCV000883979 likely benign none provided 2020-06-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004559 SCV001163641 likely pathogenic Hb SS disease criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284158 SCV001469785 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
OMIM RCV000016450 SCV000036718 other HEMOGLOBIN LA DESIRADE 2017-12-12 no assertion criteria provided literature only

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