Submissions for variant NM_000518.5(HBB):c.1A>G (p.Met1Val)

dbSNP: rs34563000

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507448	SCV000601256	pathogenic	not provided	2017-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780324	SCV000917493	pathogenic	Hemoglobinopathy	2018-02-09	criteria provided, single submitter	clinical testing	Variant summary: HBB c.1A>G alters the initiation codon (i.e. ATG coding for methionine to a triplet GTG coding for valine, so the predicted protein level name would be p.Met1Val), and it is expected that the next available, downstream ATG codon will be used as a translational start site. However, as it is out of frame (located at codons 21-22), this would result in a frameshift followed by an early termination (at the next in-frame stop codon 118 nucleotides downstream), likely leading to a missing/non-functional protein product (Hattori 1991). Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245874 control chromosomes. The c.1A>G variant has been reported in the literature in multiple individuals in the heterozygous state causing Beta Thalassemia Minor (e.g. Hattori 1991, Huisman 1997, Ohba 1997, Perea 2004, Liu 2011), however it is expected that in homozygosity and/or compound heterozygosity with a severe variant, this variant is likely to cause the BTHAL MJR phenotype. Other changes affecting the initiation codon (such as: c.2T>G (p.Met1Arg), c.2T>C (p.Met1Thr), c.3G>A (p.Met1Ile)) have also been found in HBB patients (source: HGMD). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507448	SCV001473222	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	The HBB c.1A>G; p.Met1? variant (rs34563000), also known as Met1Val or initiation codon ATG->GTG, is reported in the literature in several heterozygous individuals affected with beta-thalassemia minor (Liu 2011, Perea 2004, HbVar database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical translation initiation codon and is predicted to result in an aberrant or absent protein. Other variants that affect the HBB initiation codon have been reported in individuals with beta-thalassemia or microcytic anemia and are considered pathogenic (HbVar database and references therein). Based on available information, the c.1A>G variant is considered to be pathogenic. References: Link to c.1A>G in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=775 Liu SC et al. Molecular lesion frequency of hemoglobin gene disorders in Taiwan. Hemoglobin. 2011;35(3):228-36. Perea FJ et al. Molecular spectrum of beta-thalassemia in the Mexican population. Blood Cells Mol Dis. 2004 Sep-Oct;33(2):150-2.
Fulgent Genetics, Fulgent Genetics	RCV005049575	SCV005684732	pathogenic	Dominant beta-thalassemia; Heinz body anemia; Hb SS disease; Malaria, susceptibility to; METHEMOGLOBINEMIA, BETA TYPE; Erythrocytosis, familial, 6; Hereditary persistence of fetal hemoglobin; Beta-thalassemia HBB/LCRB	2024-03-25	criteria provided, single submitter	clinical testing
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078261	SCV001244404	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078261	SCV002091624	pathogenic	beta Thalassemia	2017-03-17	no assertion criteria provided	clinical testing