ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.382C>A (p.Pro128Thr) (rs146601335)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235285 SCV000294177 uncertain significance not specified 2017-04-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DNMT1 gene. The P128T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P128T variant is observed in 18/66,718 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P128T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000706094 SCV000835126 uncertain significance Hereditary sensory neuropathy type IE 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 128 of the DNMT1 protein (p.Pro128Thr). The proline residue is weakly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs146601335, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DNMT1-related disease. ClinVar contains an entry for this variant (Variation ID: 246583). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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