Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000030006 | SCV000052661 | likely pathogenic | beta Thalassemia | 2011-08-18 | criteria provided, single submitter | curation | Converted during submission to Likely pathogenic. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000506003 | SCV000601332 | pathogenic | not provided | 2021-02-02 | criteria provided, single submitter | clinical testing | The HBB c.92G>A (p.Arg31Lys) variant (also known as IVS-I (-1) or Codon 30 (G>A)) changes the last nucleotide of exon 1 and is located at the exon 1-intron 1 junction. It is predicted to interfere with proper beta-globin mRNA splicing and may affect normal beta-globin mRNA production. This variant is associated with beta (0)-thalassemia (PMID: 2577233 (1989), and PMID: 19254853 (2009)). |
Counsyl | RCV000030006 | SCV000788510 | likely pathogenic | beta Thalassemia | 2017-01-26 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000506003 | SCV001576509 | likely pathogenic | not provided | 2023-07-18 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.92G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2915972, 18056002, 27828729). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36337). This variant is also known as p.Arg30Lys, codon 30 (G‚ÜíA) , IVS-I (-1). This missense change has been observed in individuals with beta thalassemia (PMID: 10815781, 26410419). This variant is present in population databases (rs33960103, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 31 of the HBB protein (p.Arg31Lys). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. |
ARUP Laboratories, |
RCV000506003 | SCV002506319 | likely pathogenic | not provided | 2022-01-12 | criteria provided, single submitter | clinical testing | The IVS-I (-1) or codon 30 (G->A) variant (HBB: c.92G>A; p.Arg31Lys, also known as Arg30Lys when numbered from the mature protein, HbVar ID: 816, rs33960103) is reported in the compound heterozygous state in individuals affected with beta (0) thalassemia (see link to HbVar, Kalaydjieva 1989, Maazoun 2016, Muniz 2000). This variant is also reported in ClinVar (Variation ID: 36337), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the last nucleotide of exon 1 and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by severely weakening the nearby canonical donor splice site. Additionally, another variant at this nucleotide (Hb Monroe variant, c.92G>C; p.Arg31Thr, HbVar ID: 290) has been reported in individuals with beta (0) thalassemia, is shown to affect splicing, and is considered pathogenic (Vidaud 1989). Based on available information, the p.Arg31Lys variant is considered to be likely pathogenic. References: Link to HbVar for IVS-I (-1): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=816 Kalaydjieva L et al. The molecular basis of beta thalassaemia in Bulgaria. J Med Genet. 1989 Oct;26(10):614-8. PMID: 2577233. Maazoun F et al. Symptomatic extramedullary haematopoiesis in beta-thalassemia: A retrospective single centre study. Rev Med Interne. 2016 Jan;37(1):5-12. French. PMID: 26410419. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Vidaud M et al. A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1041-5. PMID: 2915972. |
The ITHANET community portal, |
RCV000030006 | SCV001244509 | pathogenic | beta Thalassemia | 2019-11-25 | no assertion criteria provided | curation | |
Natera, |
RCV000030006 | SCV001453787 | likely pathogenic | beta Thalassemia | 2020-09-16 | no assertion criteria provided | clinical testing |