Submissions for variant NM_000355.4(TCN2):c.809C>T (p.Ala270Val)

gnomAD frequency: 0.00056  dbSNP: rs201392026

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000635258	SCV000756645	uncertain significance	Transcobalamin II deficiency	2022-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the TCN2 protein (p.Ala270Val). This variant is present in population databases (rs201392026, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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: 529778). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000635258	SCV000899017	uncertain significance	Transcobalamin II deficiency	2021-03-30	criteria provided, single submitter	clinical testing	TCN2 NM_000355.3 exon 6 p.Ala270Val (c.809C>T): This variant has not been reported in the literature but is present in 0.1% (37/18870) of East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/22-31011643-C-T). This variant is present in ClinVar (Variation ID:529778). Evolutionary conservation and computational predictive tools for this variant are unclear; of note, computational tools designed to predict splicing suggest a potential effect from this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724109	SCV001955272	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724109	SCV001971049	uncertain significance	not provided		no assertion criteria provided	clinical testing