Submissions for variant NM_000355.3(TCN2):c.497_498del (p.Leu166Profs)

dbSNP: rs778381859

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000431820	SCV000510874	pathogenic	not provided	2016-10-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624115	SCV000740821	uncertain significance	Inborn genetic diseases	2015-02-05	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Eurofins Ntd Llc (ga)	RCV000431820	SCV000860810	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000779370	SCV000915971	likely pathogenic	Transcobalamin II deficiency	2018-10-19	criteria provided, single submitter	clinical testing	The TCN2 c.497_498delTC (p.Leu166ProfsTer7) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu166ProfsTer7 variant has been reported in two studies and is found in a total of four unrelated individuals with transcobalamin II deficiency, including in three in a homozygous state and in one in a compound heterozygous state (Schiff et al. 2010; Trakadis et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00048 in the African population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Leu166ProfsTer7 variant is classified as likely pathogenic for transcobalamin II deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779370	SCV000935283	pathogenic	Transcobalamin II deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu166Profs*7) 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 variant is present in population databases (rs778381859, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with transcobalamin deficiency (PMID: 20352340). ClinVar contains an entry for this variant (Variation ID: 376919). For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000779370	SCV001190483	pathogenic	Transcobalamin II deficiency	2021-03-30	criteria provided, single submitter	clinical testing	TCN2 NM_000355.3 exon 4 p.Leu166Profs*7 (c.497_498del): This variant has been reported in the literature in at least 4 individuals with Transcobalamin II Deficiency; 3 of these individuals were homozygous, 1 was a compound heterozygote who was identified to have an additional likely disease causing variant in the TCN2 gene (Schiff 2010 PMID:20352340, Trakadis 2014 PMID:24305960). This variant is present in 0.2% (7/24962) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/22-31010402-GTC-G). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:376919). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of 2 nucleotides at position 497 which results in a premature stop codon 7 amino acids downstream from this location which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Li 1994 PMID:7980584). In summary, this variant is classified as pathogenic.
GeneDx	RCV000431820	SCV002526458	pathogenic	not provided	2023-05-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30041674, 20352340, 24305960, 32841161)