ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-12T>C

gnomAD frequency: 0.00003  dbSNP: rs781604042
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000151 SCV001156636 likely pathogenic not specified 2018-09-27 criteria provided, single submitter clinical testing The c.[316-12T>C; 316-7C>A] complex variant is reported in the literature in multiple individuals as a very mild beta + thalassemia trait (Belisario 2015, Waye 2013), and has been found in trans with Hb S and Hb C in patients with clinical symptoms (Cross 2007, Belisario 2015, Waye 2013). The c.316-12T>C variant (rs755236703) is only observed on three alleles in the Genome Aggregation Database. The c.316-7C>A variant (rs34483965) is only observed on one allele in the Genome Aggregation Database. These are intronic variants in weakly conserved nucleotides, and computational analyses (Alamut v.2.11) predict that each variant may impact splicing by weakening the nearby canonical acceptor splice site, however, without mRNA analysis it is unclear how the combination of the two variants impact splicing. Based on available information, the c.[316-12T>C; 316-7C>A] complex variant is considered to be likely pathogenic. References: Belisario A et al. Very mild forms of Hb S/beta(+)-thalassemia in Brazilian children. Rev Bras Hematol Hemoter. 2015 37(3):198-201. Cross T et al. Sickle liver disease--an unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation. Am J Hematol. 2007 82(9):852-4. Waye J et al. Mild beta(+)-thalassemia associated with two linked sequence variants: IVS-II-839 (T>C) and IVS-II-844 (C>A). Hemoglobin. 2013 37(4):378-86.
Labcorp Genetics (formerly Invitae), Labcorp RCV001419630 SCV001621890 likely benign not provided 2023-08-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001000151 SCV003929038 likely benign not specified 2025-01-08 criteria provided, single submitter clinical testing Variant summary: HBB c.316-12T>C alters a conserved nucleotide located at a position not widely known to affect splicing. 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 1.2e-05 in 250956 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.316-12T>C (legacy name IVS-II-839T>C) has been reported in the literature as a complex allele in cis with c.316-7C>A (legacy name IVS-II-844C>A) in individuals affected with mild Beta Thalassemia (example, Waye_2013, Belisario_2013). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Beta 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: 26041423, 23651435). ClinVar contains an entry for this variant (Variation ID: 810861). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001419630 SCV005625764 uncertain significance not provided 2024-07-12 criteria provided, single submitter clinical testing The HBB c.316-12T>C and c.316-7C>A variants have been reported in the published literature as a complex allele in individuals with mild beta(+)-thalassemia (PMIDs: 26041423 (2015) and 23651435 (2013)). A functional study demonstrated that this variant affects the consensus splice site and interfere with processing of the primary mRNA transcript (PMID: 23651435 (2013)). The frequency in the general population, (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this complex allele is classified as likely pathogenic.

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