Submissions for variant NM_000558.3(HBA1):c.49A>G (p.Lys17Glu)

dbSNP: rs41407250

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001811176	SCV000601196	uncertain significance	not provided	2024-01-30	criteria provided, single submitter	clinical testing	The HBA1 c.49A>G (p.Lys17Glu) variant has been reported in the published literature to have normal stability, with oxygen equilibrium and kinetic properties similar to wild type Hb A (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), PMID: 4444049 (1974)). Individuals who are heterozygous for this variant have a normal clinical presentation (PMIDs: 23806067 (2013), 6085353 (1984), 740406 (1978)). Co-occurrence of this variant with a beta-thalassemia pathogenic variant presented with mild hypochromic microcytic anemia (PMID: 19234704 (2009)). The frequency of this variant in the general population, 0.000006 (1/166854 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811176	SCV001472100	likely benign	not provided	2024-06-12	criteria provided, single submitter	clinical testing	The Hb I variant (HBA1 or HBA2: c.49A>G; p.Lys17Glu, also known as Lys16Glu when numbered from the mature protein, rs41407250, HbVar ID: 19) has been reported in the literature as a stable hemoglobin variant present in normal heterozygous individuals (Arya 2009, Lin 2013, Molchanova 1994, HbVar database and references therein) and in an individual without clinical symptoms who also carried an alpha globin deletion (Liebhaber 1984). The variant is listed in ClinVar (Variation ID: 15746) and is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict the variant is deleterious (REVEL: 0.732). At least one report suggests this variant may interfere with measurements of Hb A1c in diabetic individuals (Arya 2009). Considering available information, the Hb I variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Arya V et al. Rare hemoglobin variant Hb I Philadelphia in North Indian family. Ann Hematol. 2009;88(9):927-929. PMID: 19234704. Liebhaber S et al. Hemoglobin I mutation encoded at both alpha-globin loci on the same chromosome: concerted evolution in the human genome. Science. 1984; 226(4681):1449-51. PMID: 6505702. Lin M et al. Molecular epidemiological survey of hemoglobinopathies in the Wuxi region of Jiangsu Province, eastern China. Hemoglobin. 2013;37(5):454-466. PMID: 23806067. Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994;88(2):300-306. PMID: 7803274.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507468	SCV004037877	likely benign	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: HBA1 c.49A>G (p.Lys17Glu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-06 in 166854 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.49A>G variant (aka Hemoglobin I, Hb I Burlington), is a known hemoglobin variant with altered electrophoretic mobility, and was reported in several asymptomatic heterozygotes, who had no hematological abnormalities (e.g. Saito_1984, Fleming_1978, Arya_2009, Lin_2013). To our knowledge, no homozygous occurrences, or compound heterozygotes with pathogenic HBA1 (or HBA2) variants were reported. The variant was reported in combination with a pathogenic HBB variant, however this individual was only mildly anemic, with a mild hypochromia and microcytosis, which are consistent with the beta-thalassemia carrier state (Arya_2009). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the oxygen equilibrium and kinetic properties of hemoglobin I were indistinguishable from those of the WT (McDonald_1974). Studies also reported that the variant might (slightly) interfere with the measurement of glycosylated hemoglobin (HbA1c) that laboratories should be aware of to avoid mismanagement of individuals carrying this variant (Arya_2009, Zechmeister_2022). The following publications have been ascertained in the context of this evaluation (PMID: 4444049, 6085353, 740406, 19234704, 23806067, 35378091, 5480848). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000017051	SCV000037323	other	HEMOGLOBIN I	2018-05-10	no assertion criteria provided	literature only
OMIM	RCV000017052	SCV000037324	other	HEMOGLOBIN I (BURLINGTON)	2018-05-10	no assertion criteria provided	literature only
OMIM	RCV000017053	SCV000037325	other	HEMOGLOBIN I (PHILADELPHIA)	2018-05-10	no assertion criteria provided	literature only
OMIM	RCV000017054	SCV000037326	other	HEMOGLOBIN I (SKAMANIA)	2018-05-10	no assertion criteria provided	literature only
OMIM	RCV000017055	SCV000037327	other	HEMOGLOBIN I (TEXAS)	2018-05-10	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004755738	SCV005351472	likely benign	HBA1-related disorder	2024-09-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).