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

Total submissions: 10

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