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

gnomAD frequency: 0.00003  dbSNP: rs34690599

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029978	SCV000052633	pathogenic	beta Thalassemia	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Eurofins Ntd Llc (ga)	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	2021-06-08	criteria provided, single submitter	clinical testing	The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506445	SCV000603910	pathogenic	not provided	2023-11-15	criteria provided, single submitter	clinical testing	The HBB c.316-106C>G variant (rs34690599, HbVar ID: 891), also known as IVS-II-745 C>G, is reported in the heterozygous state in individuals with beta(+) thalassemia minor and in the homozygous and compound heterozygous state in individuals with transfusion-dependent beta-thalassemia major (Orkin 1982, Ropero 2013, HbVar database). Functional characterization of the variant indicates an accumulation of beta globin transcript containing intron 2 sequences (Orkin 1982). This variant is also reported 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: https://globin.bx.psu.edu/hbvar/menu.html 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. PMID: 6280057. 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. PMID: 23425204.
Fulgent Genetics, Fulgent Genetics	RCV002476980	SCV000893885	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; alpha Thalassemia; Malaria, susceptibility to; Methemoglobinemia, beta-globin type; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2022-04-26	criteria provided, single submitter	clinical testing
Invitae	RCV000506445	SCV000939450	pathogenic	not provided	2024-01-06	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. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 55 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with β-thalassemia (PMID: 2713503, 11559932, 23425204, 25155404). This variant is also known as IVS-II-745C>G or IVS2-745C>G. ClinVar contains an entry for this variant (Variation ID: 15457). Studies have shown that this variant alters HBB gene expression (PMID: 6188062). Studies have shown that this variant results in the activation of a cryptic splice site in intron 2 (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 Genetics, 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.
Centogene AG - the Rare Disease Company	RCV000029978	SCV001426612	pathogenic	beta Thalassemia		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000506445	SCV001714965	pathogenic	not provided	2020-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000506445	SCV002024970	pathogenic	not provided	2021-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000506445	SCV002513695	pathogenic	not provided	2022-05-15	criteria provided, single submitter	clinical testing	No data available from control populations to assess the frequency of this variant; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 2375910, 22975760, 19657842, 6280057, 23425204, 2200760, 25408857, 32860008, 11559932, 2713503, 25155404, 9163586)
Genetics and Molecular Pathology, SA Pathology	RCV002272021	SCV002556937	pathogenic	Dominant beta-thalassemia	2020-02-21	criteria provided, single submitter	clinical testing	PS3, PM2, PM3, PP4, PP5.
MGZ Medical Genetics Center	RCV002288505	SCV002581690	pathogenic	Beta-thalassemia HBB/LCRB	2022-08-05	criteria provided, single submitter	clinical testing
OMIM	RCV000016715	SCV000036985	pathogenic	Beta-plus-thalassemia	1982-04-15	no assertion criteria provided	literature only
GeneReviews	RCV000029978	SCV000040709	not provided	beta Thalassemia		no assertion provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000029978	SCV001244410	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000029978	SCV002089195	pathogenic	beta Thalassemia	2020-11-03	no assertion criteria provided	clinical testing