ClinVar Miner

Submissions for variant NM_000355.4(TCN2):c.1127dup (p.Leu376fs)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital RCV002508873 SCV002818148 pathogenic not provided 2022-12-17 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003598143 SCV004381494 pathogenic Transcobalamin II deficiency 2023-01-16 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 1810225). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the TCN2 protein in which other variant(s) (p.Arg399*) have been determined to be pathogenic (PMID: 18956254, 31666257). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with TCN2-related conditions. This variant is present in population databases (rs747615809, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Leu376Phefs*36) in the TCN2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the TCN2 protein.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV003598143 SCV005088244 pathogenic Transcobalamin II deficiency 2024-07-23 criteria provided, single submitter clinical testing The variant is a null variant causing frameshift (PVS1 - strong). This and other similar null variants have been reported to be causative (PM1, PMID:36703223, 20352340). The variant is rare in the healthy population (PM2-supporting). The clinical test in combination with phenotye allows for use of PP4 - strong (based on Biesecker et al. 2024 ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria, PMID: 38103548).

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