Submissions for variant NM_000518.5(HBB):c.130G>T (p.Glu44Ter)

dbSNP: rs33922842

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506797	SCV000601241	pathogenic	not provided	2021-08-19	criteria provided, single submitter	clinical testing	The c.130G>T (p.Glu44*) pathogenic variant (also known as Codon 43 (G>T)) causes the premature termination of beta globin protein synthesis, and is associated with beta(0)-thalassemia PMIDs: 3403716 (1988), 17008283 (2006), 25000193 (2014)).
Counsyl	RCV000665678	SCV000789837	pathogenic	beta Thalassemia	2017-02-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506797	SCV000883991	pathogenic	not provided	2018-02-08	criteria provided, single submitter	clinical testing	The HBB c.130G>T; Glu43Ter variant (rs33922842), also known as Codon 43 (G>T), is reported in the medical literature in an individual with beta thalassemia who also carried an additional nonsense variant on the opposite chromosome (Atweh 1988, see link to HbVar below). The variant is described as pathogenic in the ClinVar database (Variation ID: 15406). The variant is also listed in the Genome Aggregation Database in 1 out of 246166 alleles. This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In agreement with that prediction, this variant is shown to have reduced mRNA levels when transfected and absent mRNA levels in cells derived from the individual who carried this variant and an additional nonsense variant on the opposite chromosome (Athweh 1988). Considering available information, this variant is classified as pathogenic. References: Link to Glu43Ter in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=853&.cgifields=histD Atweh GF et al. New amber mutation in a beta-thalassemic gene with nonmeasurable levels of mutant messenger RNA in vivo. J Clin Invest. 1988 Aug;82(2):557-61.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780310	SCV000917477	pathogenic	Hemoglobinopathy	2017-11-14	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.130G>T (p.Glu44X) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.176delC, c.217dupA, c.287dupA, etc.). This variant was found in 1/246166 control chromosomes at a frequency of 0.0000041 (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been found three Chinese BTHAL patients in compound heterozygous state with other pathogenic variants (Atwen_1988, Tan_2006). Two of them were BTHAL major patients who carried this variant in compound heterozygous state with c.127_130delCTTT. In addition, several BTHAL minor individuals who carry this variant in heterozygous state have been reported (Lin_2014, He_2017). The carrier frequency in a large Chinese population was 0.03% (He_2017). A functional analysis showed that the mutant mRNA in vivo must be extremely low (Atwen_1988). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV001004568	SCV001163652	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Invitae	RCV000506797	SCV001410344	pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu44*) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33922842, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with beta-thalassemia (PMID: 3403716, 25089872). This variant is also known as p.Glu43*. ClinVar contains an entry for this variant (Variation ID: 15406). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000506797	SCV002559381	pathogenic	not provided	2022-02-04	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30275481, 31690135, 3403716, 17008283)
OMIM	RCV000016660	SCV000036929	pathogenic	Beta zero thalassemia	1988-08-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV000665678	SCV001244550	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV000665678	SCV002089223	pathogenic	beta Thalassemia	2020-10-19	no assertion criteria provided	clinical testing