Submissions for variant NM_000518.5(HBB):c.112del (p.Trp38fs)

dbSNP: rs63750532

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508367	SCV000601234	pathogenic	not provided	2021-07-28	criteria provided, single submitter	clinical testing	The HBB c.112del (p.Trp38Glyfs*24) variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia and has been reported in individuals with beta thalassemia (PMIDs: 32190157 (2020), 2197725 (1990), 1986379 (1991) 28391758 (2017), 31134759 (2019), 26084319 (2015)). Previous names for this variant include Codons 36/37 (-T) and CCT TGG (Pro-Trp). Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781455	SCV000919491	pathogenic	Hemoglobinopathy	2018-01-09	criteria provided, single submitter	clinical testing	Variant summary: The HBB c.112delT (p.Trp38GlyfsX24) 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. This variant is absent in 30964 control chromosomes (gnomAD). Multiple publications have cited the variant in individuals affected with BTHAL, observed predominantly in middle eastern countries (Rund_1991, El-Kalla_1997, Huisman_1997). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508367	SCV001156652	pathogenic	not provided	2021-01-07	criteria provided, single submitter	clinical testing	The HBB c.112delT; p.Trp38fs variant (rs63750532), also known as Codons 36/37 (-T) or Frameshift 36/37, is described in the literature in individuals with thalassemia who also carried another pathogenic variant (Rund 1991). This variant is reported as pathogenic in ClinVar (15431). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Link to c.112delT variant in HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=840&.cgifields=histD Rund D et al. Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):310-4.
Baylor Genetics	RCV001004345	SCV001163280	pathogenic	Hb SS disease		criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001078307	SCV001251903	pathogenic	beta Thalassemia	2020-05-03	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000508367	SCV001449909	pathogenic	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Invitae	RCV000508367	SCV001578260	pathogenic	not provided	2023-04-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15431). This variant is also known as nonsense 39. This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 1986379, 28391758). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp38Glyfs*24) 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).
Genome-Nilou Lab	RCV001078307	SCV001810471	pathogenic	beta Thalassemia	2021-07-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504797	SCV002795144	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	2022-04-13	criteria provided, single submitter	clinical testing
OMIM	RCV000016688	SCV000036947	pathogenic	Beta zero thalassemia	1991-01-01	no assertion criteria provided	literature only
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078307	SCV001244471	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078307	SCV002089229	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing