Submissions for variant NM_000355.4(TCN2):c.1237A>G (p.Arg413Gly)

gnomAD frequency: 0.00075  dbSNP: rs148963479

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635256	SCV000756643	uncertain significance	Transcobalamin II deficiency	2022-10-17	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 413 of the TCN2 protein (p.Arg413Gly). This variant is present in population databases (rs148963479, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. 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: 529776). 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. 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.
Illumina Laboratory Services, Illumina	RCV000635256	SCV001311219	uncertain significance	Transcobalamin II deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Revvity Omics, Revvity	RCV000635256	SCV003827146	uncertain significance	Transcobalamin II deficiency	2021-04-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003424207	SCV004154864	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	TCN2: BP4
PreventionGenetics, part of Exact Sciences	RCV003928068	SCV004746715	likely benign	TCN2-related disorder	2019-09-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).