Submissions for variant NM_000355.4(TCN2):c.1195C>G (p.Arg399Gly)

dbSNP: rs769817524

Total submissions: 2

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	RCV000768104	SCV000899019	uncertain significance	Transcobalamin II deficiency	2021-03-30	criteria provided, single submitter	clinical testing	TCN2 NM_000355.3 exon 8 p.Arg399Gly (c.1195C>G): This variant has not been reported in the literature, and it is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant are insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000768104	SCV003033195	uncertain significance	Transcobalamin II deficiency	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 399 of the TCN2 protein (p.Arg399Gly). This variant is not present in population databases (gnomAD no frequency). 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: 626029). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.