ClinVar Miner

Submissions for variant NM_001062.4(TCN1):c.683T>C (p.Ile228Thr)

gnomAD frequency: 0.00009  dbSNP: rs143824687
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001051357 SCV001215505 uncertain significance Transcobalamin I deficiency 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 228 of the TCN1 protein (p.Ile228Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs143824687, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with TCN1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine 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.
Ambry Genetics RCV004031596 SCV004072107 uncertain significance not specified 2023-06-27 criteria provided, single submitter clinical testing The c.683T>C (p.I228T) alteration is located in exon 5 (coding exon 5) of the TCN1 gene. This alteration results from a T to C substitution at nucleotide position 683, causing the isoleucine (I) at amino acid position 228 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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