ClinVar Miner

Submissions for variant NM_000517.6(HBA2):c.146T>G (p.Leu49Arg)

gnomAD frequency: 0.00001  dbSNP: rs41392146
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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 RCV000759782 SCV000889348 uncertain significance not provided 2020-11-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000759782 SCV001473499 uncertain significance not provided 2023-09-22 criteria provided, single submitter clinical testing The Hb Montgomery variant (HBA2: c.146T>G; p.Leu49Arg, also known as Leu48Arg when numbered from the mature protein, rs41392146, HbVar ID: 69), is reported in the literature in individuals with no associated clinical symptoms, and is considered a stable hemoglobin variant (Molchanova 1994, HbVar and references therein). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. This variant is reported in ClinVar (Variation ID: 15637), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 49 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.754). Due to limited information, the clinical significance of the Hb Montgomery variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Molchanova T et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 88(2):300-6. PMID: 7803274.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689421 SCV005185616 uncertain significance not specified 2024-05-17 criteria provided, single submitter clinical testing Variant summary: HBA2 c.146T>G (p.Leu49Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.146T>G has been reported in the literature as a stable hemoglobin variant in asymptomatic individuals (e.g. Brimhall_1975, Molchanova_1994). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 7803274, 1115799). ClinVar contains an entry for this variant (Variation ID: 15637). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM RCV000016914 SCV000037185 other HEMOGLOBIN MONTGOMERY 2023-09-05 no assertion criteria provided literature only
OMIM RCV000016915 SCV000037186 other HEMOGLOBIN BIRMINGHAM (USA) 2023-09-05 no assertion criteria provided literature only
Natera, Inc. RCV001826471 SCV002093845 uncertain significance alpha Thalassemia 2018-11-01 no assertion criteria provided clinical testing

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