ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.316-106C>G (rs34690599)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029978 SCV000052633 pathogenic beta Thalassemia 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000506445 SCV000331532 pathogenic not provided 2016-07-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506445 SCV000601275 pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506073 SCV000603910 pathogenic not specified 2018-08-02 criteria provided, single submitter clinical testing The HBB c.316-106C>G variant (rs34690599), also known as IVS-II-745 (C>G), is reported in multiple patients with beta-thalassemia (Orkin 1982, Ropero 2013, HbVar database). Functional characterization of the variant indicates an accumulation of beta globin transcript containing intron 2 sequences (Orkin 1982), and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15457). This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a cryptic donor splice site, consistent with the observed phenotype in functional studies. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database for IVS-II-745(C->G): Orkin S et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982; 296(5858):627-31. Ropero P et al. Association in cis of the mutations +20 (C>T) in the 5' untranslated region and IVS-II-745 (C>G) on the beta-globin gene. Hemoglobin. 2013; 37(2):112-8.
Fulgent Genetics,Fulgent Genetics RCV000763248 SCV000893885 pathogenic Beta-thalassemia, dominant inclusion body type; Fetal hemoglobin quantitative trait locus 1; Heinz body anemia; Hb SS disease; alpha Thalassemia; Susceptibility to malaria; beta Thalassemia; Methemoglobinemia, beta-globin type; Erythrocytosis 6, familial 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000506445 SCV000939450 pathogenic not provided 2019-12-10 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed as homozygous or in combination with another HBB variant in individuals affected with -thalassemia (PMID: 23425204, 25155404, 2713503, 11559932). This variant is also known as IVS-II-745C>G or IVS2-745C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 15457). Experimental studies have shown that this intronic change affects RNA splicing leading to an aberrant transcript (PMID: 6188062). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001004564 SCV001163648 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000029978 SCV001194216 pathogenic beta Thalassemia 2019-12-09 criteria provided, single submitter clinical testing NM_000518.4(HBB):c.316-106C>G(aka IVS2-745C>G) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 11559932 and 6188062. Classification of NM_000518.4(HBB):c.316-106C>G(aka IVS2-745C>G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
OMIM RCV000016715 SCV000036985 pathogenic Beta-plus-thalassemia 1982-04-15 no assertion criteria provided literature only
GeneReviews RCV000029978 SCV000040709 pathogenic beta Thalassemia 2015-05-14 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000029978 SCV000678141 pathogenic beta Thalassemia 2015-08-28 no assertion criteria provided clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000029978 SCV001244410 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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