ClinVar Miner

Submissions for variant NM_000355.4(TCN2):c.809C>T (p.Ala270Val) (rs201392026)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000635258 SCV000756645 uncertain significance Transcobalamin II deficiency 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 270 of the TCN2 protein (p.Ala270Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs201392026, ExAC 0.2%). This variant has not been reported in the literature in individuals with TCN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000635258 SCV000899017 uncertain significance Transcobalamin II deficiency 2018-08-07 criteria provided, single submitter clinical testing TCN2 NM_000355.3 exon 6 p.Ala270Val (c.809C>T): This variant has not been reported in the literature but is present in 0.1% (37/18870) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/22-31011643-C-T). This variant is present in ClinVar (Variation ID:529778). Evolutionary conservation and computational predictive tools for this variant are unclear; of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

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