ClinVar Miner

Submissions for variant NM_000355.3(TCN2):c.497_498del (p.Leu166Profs) (rs778381859)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624115 SCV000740821 uncertain significance Inborn genetic diseases 2015-02-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000431820 SCV000510874 pathogenic not provided 2016-10-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000431820 SCV000860810 pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779370 SCV000915971 likely pathogenic Transcobalamin II deficiency 2018-10-19 criteria provided, single submitter clinical testing The TCN2 c.497_498delTC (p.Leu166ProfsTer7) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu166ProfsTer7 variant has been reported in two studies and is found in a total of four unrelated individuals with transcobalamin II deficiency, including in three in a homozygous state and in one in a compound heterozygous state (Schiff et al. 2010; Trakadis et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00048 in the African population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Leu166ProfsTer7 variant is classified as likely pathogenic for transcobalamin II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000779370 SCV000935283 pathogenic Transcobalamin II deficiency 2018-09-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu166Profs*7) in the TCN2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs778381859, ExAC 0.05%). This variant has been observed in individuals affected with transcobalamin deficiency (PMID: 20352340). Loss-of-function variants in TCN2 are known to be pathogenic (PMID: 7980584, 20352340). For these reasons, this variant has been classified as Pathogenic.

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