ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.803C>T (p.Pro268Leu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686192 SCV000813697 uncertain significance Hereditary sensory neuropathy type IE 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 268 of the DNMT1 protein (p.Pro268Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs779634956, ExAC 0.001%). This variant has not been reported in the literature in individuals with DNMT1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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