ClinVar Miner

Submissions for variant NM_000355.4(TCN2):c.1235A>G (p.Tyr412Cys)

dbSNP: rs745363222
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768105 SCV000899020 uncertain significance Transcobalamin II deficiency 2021-03-30 criteria provided, single submitter clinical testing TCN2 NM_000355.3 exon 9 p.Tyr412Cys (c.1235A>G): This variant has not been reported in the literature but is present in 0.006% (2/30614) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/22-31022459-A-G). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV000768105 SCV005690915 uncertain significance Transcobalamin II deficiency 2024-06-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 412 of the TCN2 protein (p.Tyr412Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TCN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 626030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TCN2 protein function with a positive predictive value of 80%. 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.

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