ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.856G>A (p.Val286Met) (rs368960099)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657954 SCV000779724 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DNMT1 gene. The V286M variant has not been published in association with neuropathy to our knowledge. The V286M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the V286M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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 RCV000692423 SCV000820248 uncertain significance Hereditary sensory neuropathy type IE 2018-04-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 286 of the DNMT1 protein (p.Val286Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs368960099, ExAC 0.01%). 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 methionine 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. 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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