ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.-31C>T (rs63750628)

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Total submissions: 8
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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 RCV001420720 SCV000052611 likely benign not specified 2021-04-23 criteria provided, single submitter clinical testing Variant summary: HBB c.-31C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 6.4e-05 in 250664 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.-31C>T has been widely reported in the literature to co-occur in cis with other disease causing variants such as IVS-II-745C>G (c.316-106C>G) in individuals affected with Beta Thalassemia (example, Gonzalez-Redondo_1989, Lemsaddek_2003, Yavarian_2001, Galehdari_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Beta Thalassemia. Locus specific databases report this variant predominantly as benign. At least one publication reports experimental evidence evaluating an impact on expression of beta globin mRNA, however, does not allow convincing conclusions about the variant effect (example, Irenge_2002). Five clinical diagnostic laboratories and a database (ITHANET) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (benign, n=2; likely benign; n=1, VUS, n=3). One submitter reports both a benign and VUS classifications. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507019 SCV000603911 likely benign none provided 2020-07-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755548 SCV000888153 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000029956 SCV000914521 uncertain significance beta Thalassemia 2018-12-05 criteria provided, single submitter clinical testing The HBB c.-31C>T variant, commonly referred to as 5’UTR+20, C>T, has been described in at least four studies in which it is found in cis with the same intronic variant, c.316-106C>G (commonly referred to as IVS-II-745 (C>G)). The c.-31C>T variant was found in a homozygous state in three individuals with a severe form of beta-thalassemia, in a compound heterozygous state in an additional three individuals with the same severe phenotype, and in a heterozygous state in six individuals, all with a milder phenotype. In all cases, the c.-31C>T variant was in cis with the intronic variant (Yavarian et al. 2001; Liaw et al. 2009; Ropero et al. 2013; Farashi et al. 2015). Sirdah et al. (2013) also reported the c.-31C>T variant in a compound heterozygous state in one individual with beta-thalassemia who did not carry the intronic variant. The c.-31C>T variant is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the c.-31C>T variant is classified as a variant of unknown significance for HBB-related disorders.
Illumina Clinical Services Laboratory,Illumina RCV001104361 SCV001261218 benign Hb SS disease 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001104362 SCV001261220 uncertain significance Fetal hemoglobin quantitative trait locus 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001104363 SCV001261221 benign Hemoglobin E 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029956 SCV001244457 benign beta Thalassemia 2019-11-25 no assertion criteria provided curation

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