Submissions for variant NM_000355.4(TCN2):c.679C>T (p.Arg227Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003494767	SCV004298858	pathogenic	Transcobalamin II deficiency	2023-09-26	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg227*) in the TCN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCN2 are known to be pathogenic (PMID: 7980584, 20352340). This premature translational stop signal has been observed in individual(s) with clinical features of transcobalamin II deficiency (PMID: 26827111). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003494767	SCV005073838	likely pathogenic	Transcobalamin II deficiency		criteria provided, single submitter	clinical testing	The stop gained variant c.679C>T (p.Arg227Ter) in the TCN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has 0.0003% allele frequency in gnomAD Exomes. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing (Zhan et al., 2020). For these reasons, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003909040	SCV004734554	pathogenic	TCN2-related disorder	2023-10-21	no assertion criteria provided	clinical testing	The TCN2 c.679C>T variant is predicted to result in premature protein termination (p.Arg227*). This variant has been reported in the homozygous state in multiple individuals with transcobalamin II deficiency, including two siblings whose parents were found to be heterozygous carriers (Table 3, Pupavac M et al. 2016. PubMed ID: 26827111; Table 1, Nashabat M et al. 2017. PubMed ID: 28538514). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-31011386-C-T). Nonsense variants in TCN2 are expected to be pathogenic. This variant is interpreted as pathogenic.