ClinVar Miner

Submissions for variant NM_000518.5(HBB):c.397A>C (p.Lys133Gln) (rs33953406)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780329 SCV000917500 likely benign not specified 2018-11-20 criteria provided, single submitter clinical testing Variant summary: HBB c.397A>C (p.Lys133Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246104 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.397A>C has been reported in the literature from many African countries, reported mainly in the people of the Akan group in West Africa, found predominantly in the Attie subgroup (Ali 2015), which may explain its absence in the gnomAD database due to insufficient coverage of that ethnic group. Several families were reported with heterozygotes and at least one family with a homozygote individual, with none of them expressing any clinical manifestation or hematological abnormality (Ringelhann 1971, Cabannes 1980, Zago 1986, Ali 2015). In addition, functional studies have shown that there were no morphological changes in the red blood cells of heterozygotes, osmotic fragility was within the normal range (Ringelhann 1971), and the variant resulted in no globin chain synthesis imbalance in reticulocytes (Zago 1986). ClinVar has got an entry for the variant, without a classification specified. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000780329 SCV001159606 likely benign not specified 2019-03-01 criteria provided, single submitter clinical testing The Hb K-Woolwich variant (HBB: c.397A>C; p.Lys133Gln, also known as Lys132Gln when numbered from the mature protein; rs33953406) is reported in the literature in an individual affected with beta thalassemia (Lang 1974) but is also described in multiple healthy individuals carrying the variant in the homozygous state or in trans to the Hb S variant (Ali 2015, Cabannes 1980, Sharma 2014, Zago 1986, HbVar database). While this variant was reported to segregate with slightly elevated HbA2 levels in one family, this family presented with other hematological anomalies, including members with alpha thalassemia and others carrying the Hb S sickle cell variant (Lang 1974). In vitro assays indicate that the p.Lys133Gln variant has normal solubility and stability (Cabannes 1980, HbVar database), though it is present at slightly lower levels than wildtype in vivo (Cabannes 1980, Lang 1974), and analysis of p.Lys133Gln protein synthesis rates are inconclusive (Lang 1974, Zago 1986). This variant is reported in ClinVar (Variation ID: 15233), but is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The lysine at codon 132 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given its presence in multiple individuals with normal hematological profiles, this variant is considered to be likely benign. References: Link to HbVar database entry: Ali SA and Ali N. A Rare Haemoglobin Variant Identified as K Woolwich in a Pakistani Male. J Coll Physicians Surg Pak. 2015 Oct;25 Suppl 2:S100-1. Cabannes R et al. Haemoglobin K Woolwich: a study of the family of a homozygote. J Med Genet. 1980 Jun;17(3):183-6. Lang A et al. Hb K Woolwich the cause of a thalassaemia. Nature. 1974 May 31;249(456):467-9. Sharma R et al. Hemoglobin K-Woolwich (Hb KW): Its Combination with Sickle Cell Trait. Open J Pathol. 2014 May 11;4:110-115. Zago MA et al. Balanced globin synthesis by Hb K Woolwich heterozygotes. Br J Haematol. 1986 Sep;64(1):207-10.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284159 SCV001469786 likely benign not provided 2020-01-16 criteria provided, single submitter clinical testing
OMIM RCV000016431 SCV000036699 other HEMOGLOBIN K (WOOLWICH) 2017-12-12 no assertion criteria provided literature only

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