ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.-51T>C

gnomAD frequency: 0.00041  dbSNP: rs386134236
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002477022 SCV000889374 uncertain significance not provided 2022-10-11 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.0019 (46/24808 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an infant with sickle cell disease who also carried the pathogenic Hb S variant (PMID: 26658910 (2016)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect HBB mRNA splicing . 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 RCV000781449 SCV000919485 uncertain significance not specified 2023-09-19 criteria provided, single submitter clinical testing Variant summary: HBB c.-51T>C is located in the untranscribed region upstream of the HBB gene region, one nucleotide upstream from the transcription initiation site (also known as mRNA cap site). Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00017 in 280600 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.011), allowing no conclusion about variant significance. The variant, c.-51T>C, has been reported in the literature in individuals who also carried other (likely) pathogenic HBB variants (Kunz_2016, Poon_2021), however the phase was not specified. These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. 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: 26658910, 33279152). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002477022 SCV004300891 likely benign not provided 2024-01-29 criteria provided, single submitter clinical testing

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