ClinVar Miner

Submissions for variant NM_000518.4(HBB):c.68A>C (p.Glu23Ala) (rs33936254)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224041 SCV000281487 pathogenic not provided 2016-05-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000224041 SCV000697143 likely benign not provided 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The HBB c.68A>C (p.Glu23Ala, also known as Hb G Coushatta) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 57/546240 control chromosomes at a frequency of 0.0001043, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). The variant has been found in healthy Native American, Turks, Egyptian, and Sri Lankan in heterozygous or homozygous state indicating neutrality. It was also found to co-occur in cis as well as in trans with beta-thalassemia pathogenic variants (c.93-21G>A, IVS-1-1, G>A, IVS-I-5) in multiple patients, and was believed not to have any clinical impact by authors. Compound heterozygosity of the variant with a pathogenic variant resulted in beta thalasssemia trait. Based on patient phenotype, the variant at most could only be modifier without being causal. A functional study showed the variant to have normal oxygen equilibrium characteristics and heat denaturation and isopropanol tests on hemolysates did not reveal instability of the hemoglobin further supprting neutrality. Considering all evidence, the variant was classified as probably normal.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000077 SCV000885559 likely benign not specified 2018-07-02 criteria provided, single submitter clinical testing The Hb G-Coushatta variant (HBB: c.68A>C; p.Glu23Ala, also known as Glu22Ala when numbered from the mature protein, rs33936254) is reported in the heterozygous state in asymptomatic individuals (Blackwell 1967, HbVar database and references therein), and exhibits no clinical symptoms when found with a beta (0) pathogenic variant (Koseler 2013). This variant is reported in ClinVar (Variation ID: 15171), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 23 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on available information, the Hb G-Coushatta variant is considered to be likely benign. REFERENCES Link to HbVar for Hb G-Coushatta: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=266 Blackwell R et al. Hemoglobin variants in Koreans: hemoglobin G Taegu. Science. 1967 158(3804):1056-7. Koseler A et al. Molecular studies on the origin of the Hb G-Coushatta mutation in Denizli province of Turkey. Biochem Genet. 2013 51(1-2):71-5.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000224041 SCV001134236 likely benign not provided 2018-12-17 criteria provided, single submitter clinical testing
Mendelics RCV000030001 SCV001138221 benign beta Thalassemia 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000030001 SCV001264859 uncertain significance beta Thalassemia 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM RCV000016343 SCV000036611 other HEMOGLOBIN G (COUSHATTA) 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016344 SCV000036612 other HEMOGLOBIN G (SASKATOON) 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016345 SCV000036613 other HEMOGLOBIN G (HSIN-CHU) 2017-12-12 no assertion criteria provided literature only
OMIM RCV000016346 SCV000036614 other HEMOGLOBIN G (TAEGU) 2017-12-12 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000030001 SCV000052656 likely benign beta Thalassemia 2015-10-02 no assertion criteria provided clinical testing

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