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

gnomAD frequency: 0.00003  dbSNP: rs63750628

Total submissions: 12

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	2024-12-06	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 estimated 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, Ozalp_2024). 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). The following publications have been ascertained in the context of this evaluation (PMID: 18976160, 20854120, 22737496, 2713503, 20113284, 12324499, 12827652, 19657842, 20704537, 15108284, 11300348, 38708170). ClinVar contains an entry for this variant (Variation ID: 36291). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755548	SCV000603911	likely benign	not provided	2024-11-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000755548	SCV000888153	likely benign	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, 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.
Genetics and Molecular Pathology, SA Pathology	RCV002272029	SCV002556471	uncertain significance	Dominant beta-thalassemia	2020-02-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755548	SCV005329722	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	HBB: PP4, BP2, BP5
Fulgent Genetics, Fulgent Genetics	RCV005049387	SCV005684733	uncertain significance	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-05-07	criteria provided, single submitter	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029956	SCV001244457	benign	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
PreventionGenetics, part of Exact Sciences	RCV004732554	SCV005351033	uncertain significance	HBB-related disorder	2024-05-28	no assertion criteria provided	clinical testing	The HBB c.-31C>T variant is located in the 5' untranslated region. This variant has also been described in the literature as 5' UTR+20(C>T) or +20(C>T) or 5’UTR-31(C>T) or C>T at nt +20 to the Cap site or β++20 (C>T). This variant has been frequently observed on the same allele (in cis) with the disease-causing variant c.316-106C>G (a.k.a. "IVS-II-745") in multiple individuals with beta thalassemia (Table 1, footnotes, Reported as C>T at nt position +20 to the Cap site, Gonzalez-Redondo et al. 1989. PubMed ID: 2713503; Reported as β++20 (C>T), Lemsaddek et al. 2003. PubMed ID: 12827652; Table 1, n 22, Reported as IVS-II-745 (C>G)+5’UTR+20(C>T), Galehdari et al. 2010. PubMed ID: 20854120; Table 1, Reported as +20(C>T), Ropero et al. 2013. PubMed ID: 23425204; Table 1 and 2, Reported as c.-31C>T, Carrocini et al. 2017. PubMed ID: 28366028). However, it has also been observed without the c.316-106C>G variant in a severely affected individual who was potentially compound heterozygous for c.-31C>T and a second pathogenic HBB variant, c.93-21G>A [a.k.a. "IVS-1-110 (G>A)"] (Tables 3 and 4, Reported as 5’UTR;+20(C>T), c.-31C>T, and 5’UTR-31(C>T), Sirdah et al. 2013. PubMed ID: 23321370). Additionally, an in vitro RT-PCR-based study reported a ~50% reduction in HBB mRNA expression for the c.-31C>T allele (without c.316-106C>G) relative to wild type (Table 1, Reported as +20C>T, Irenge et al. 2002. PubMed ID: 12324499). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.