ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.92G>C (p.Arg31Thr) (rs33960103)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000016432 SCV000221083 pathogenic beta Thalassemia 2015-01-26 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506942 SCV000601333 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507793 SCV000603906 pathogenic not specified 2018-09-19 criteria provided, single submitter clinical testing The Hb Monroe variant (HBB: c.92G>C; p.Arg31Thr, also known as Arg30Thr when numbered from the mature protein, rs33960103) has been reported in multiple patients diagnosed with beta(0) thalassemia (Vidaud 1989, HbVar database and references therein). Functional characterization of the variant indicates aberrant splicing of the beta globin RNA, resulting in severe reductions of full-length transcripts (Vidaud 1989, Agrawal 2007). This variant is found in the general population with an overall allele frequency of 0.01% (26/251362 alleles) in the Genome Aggregation Database. This variant is located adjacent to the exon-intron junction, and computational analyses predict that the variant affects the canonical splice donor (Alamut v.2.11). Based on available information, this variant is considered to be pathogenic. REFERENCES Link to HbVar database for Hb Monroe: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=290 Agrawal M et al. Missense mutation of the last nucleotide of exon 1 (G->C) of beta globin gene not only leads to undetectable mutant peptide and transcript but also interferes with the expression of wild allele. Haematologica. 2007 Dec;92(12):1715-6. 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.
Integrated Genetics/Laboratory Corporation of America RCV000016432 SCV000697157 pathogenic beta Thalassemia 2016-07-18 criteria provided, single submitter clinical testing Variant summary: The HBB c.92G>C (p.Arg31Thr) variant involves the alteration of a conserved nucleotide located adjacent to the splice donor site in intron 1 (located in the last nucleotide of exon 1). 5/5 in silico tools predict a damaging outcome for this variant along with 5/5 splice site tools predicting the variant to inhibit the utilization of the normal splice site in intron 1. These predictions have been confirmed by functional studies demonstrating the variant to virtually abolish (98% inhibition) the utilization of the normal 5' splice site in intron 1.This variant was found in 11/121334 control chromosomes at a frequency of 0.0000907, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). It was observed in several b-thalassemia patients in either homozygosity or in compound heterozygosity with other pathogenic variants, indicating pathogenicity. In addition, multiple clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000016432 SCV000746426 pathogenic beta Thalassemia 2017-12-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004351 SCV001163286 pathogenic Hb SS disease criteria provided, single submitter clinical testing
Invitae RCV000506942 SCV001211374 pathogenic not provided 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 31 of the HBB protein (p.Arg31Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs33960103, ExAC 0.07%). This variant has been observed in several individuals affected with beta thalassemia (PMID: 27828729). This variant is also known as p.Arg30Thr and Hb Monroe in the literature. ClinVar contains an entry for this variant (Variation ID: 15234). This variant has been reported to affect HBB protein function (PMID:18056002, 2915972). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000016432 SCV000036700 pathogenic beta Thalassemia 1989-02-01 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000030007 SCV000052662 pathogenic Beta thalassemia major 2015-04-03 no assertion criteria provided clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics RCV000016432 SCV001244510 pathogenic beta Thalassemia 2019-11-25 no assertion criteria provided curation

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