{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T18:23:55Z","timestamp":1758824635945},"reference-count":16,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,4,15]],"date-time":"2016-04-15T00:00:00Z","timestamp":1460678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The clinical use of holotranscobalamin (holoTC) testing to evaluate vitamin B<jats:sub>12<\/jats:sub> status has increased in recent years. We present two patients (African Caribbean and Indian heritage), in which the holoTC assay indicated severe B<jats:sub>12<\/jats:sub> deficiency (&lt; 5 pmol\/L). Additional clinical tests revealed that these patients had normal levels of total vitamin B<jats:sub>12<\/jats:sub> in blood and unremarkable levels of two other markers of vitamin B<jats:sub>12<\/jats:sub> status, homocysteine and methylmalonic acid. We hypothesized that these patients carry a variant in the transcobalamin gene (<jats:italic>TCN2<\/jats:italic>) that influences the most widely commercially available holoTC test \u2013 Active\u2010B<jats:sub>12<\/jats:sub> (Axis\u2010Shield Diagnostics Ltd).<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Exon sequencing of the <jats:italic>TCN2<\/jats:italic> gene was carried out. Protein characterization included total transcobalamin (TCN2) detection by Western blot, and holoTC by <jats:sup>57<\/jats:sup>Co\u2010labelled B<jats:sub>12<\/jats:sub> binding followed by size fractionation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Exon sequencing of <jats:italic>TCN2<\/jats:italic> revealed both patients were homozygous for the minor allele of rs35838082 (p.R215W). Western blot and chromatographic analyses revealed that the serum of these patients contains intact transcobalamin and that this variant\u2010containing protein binds vitamin B<jats:sub>12<\/jats:sub>. The variant is rare in Caucasians (minor allele frequency (MAF) &lt; 0\u00b701) but more common in South Asians (MAF ~ 0\u00b702) and those of African origin (MAF ~ 0\u00b725).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The impeded ability to detect normal levels of holoTC in these two patients may be due to this variant interfering with the detection of holoTC by one or both of the monoclonal antibodies currently employed in the Active\u2010B<jats:sub>12<\/jats:sub> test. Laboratories should be aware of this variant and use confirmatory tests when applicable.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.12617","type":"journal-article","created":{"date-parts":[[2016,3,8]],"date-time":"2016-03-08T07:50:46Z","timestamp":1457423446000},"page":"434-439","source":"Crossref","is-referenced-by-count":10,"title":["Association of a transcobalamin II genetic variant with falsely low results for the holotranscobalamin immunoassay"],"prefix":"10.1111","volume":"46","author":[{"given":"Agata","family":"Sobczy\u0144ska\u2010Malefora","sequence":"first","affiliation":[{"name":"Nutristasis Unit (St. Thomas\u2019 Hospital) Viapath London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faith","family":"Pangilinan","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute Bethesda MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon T.","family":"Plant","sequence":"additional","affiliation":[{"name":"Medical Eye Unit Guy's and St. Thomas\u2019 NHS Foundation Trust Moorfields Eye Hospital The National Hospital for Neurology and Neurosurgery London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aneliya","family":"Velkova","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute Bethesda MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominic J.","family":"Harrington","sequence":"additional","affiliation":[{"name":"Nutristasis Unit (St. Thomas\u2019 Hospital) Viapath London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne M.","family":"Molloy","sequence":"additional","affiliation":[{"name":"School of Medicine Trinity College Dublin Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence C.","family":"Brody","sequence":"additional","affiliation":[{"name":"Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute Bethesda MD USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,4,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200052997384"},{"key":"e_1_2_9_3_1","first-page":"47","article-title":"The transport of endogenous vitamin B12 in normal human serum","volume":"51","author":"England JM","year":"1976","journal-title":"Clin Sci Mol Med"},{"key":"e_1_2_9_4_1","first-page":"453","article-title":"The carriers of native vitamin B12 in normal human serum","volume":"53","author":"Hall CA","year":"1977","journal-title":"Clin Sci Mol Med"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1515\/CCLM.2007.361"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2007.096784"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-7075-3-3"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2013.08.006"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2010.158154"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1996.0713"},{"key":"e_1_2_9_11_1","first-page":"eA311","article-title":"Development of a fully automated method for determination of methylmalonic acid in human serum\/plasma by MPS\u2010LC\u2010MS\/MS","volume":"52","author":"Gorska R","year":"2014","journal-title":"Clin Chem Lab Med"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1972.tb08784.x"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11632"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth457"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509099103"},{"key":"e_1_2_9_16_1","unstructured":"Office for National Statistics.Ethnic group local authorities in England and Wales. 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