ClinVar Miner

Submissions for variant NM_000355.4(TCN2):c.10C>T (p.Leu4Phe)

gnomAD frequency: 0.00002  dbSNP: rs572942248
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756753 SCV000884659 uncertain significance not provided 2017-08-01 criteria provided, single submitter clinical testing The variant p.Leu4Phe (rs572942248) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.003 percent (identified on 1 out of 30,968 chromosomes). The leucine at position 4 is highly conserved considering eleven species (Alamut v2.9.0) and computational analyses of the effects of the p.Leu4Phe variant on protein structure and function indicates conflicting results (SIFT: damaging, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Leu4Phe variant with certainty.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill RCV001249837 SCV001423852 uncertain significance Transcobalamin II deficiency criteria provided, single submitter research The TCN2 c.10C>T [p.Leu4Phe] missense variant is predicted to change a single amino acid. This variant has not been reported previously in the literature and is considered a variant of uncertain clinical significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001249837 SCV001485326 uncertain significance Transcobalamin II deficiency 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 4 of the TCN2 protein (p.Leu4Phe). This variant is present in population databases (rs572942248, gnomAD no frequency). 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: 618417). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.

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