ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.341G>A (p.Arg114Lys) (rs554894511)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235913 SCV000293800 uncertain significance not provided 2016-01-18 criteria provided, single submitter clinical testing The R114K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in the 1000 Genomes Project, and it was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the R114K 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. In silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000807203 SCV000947245 uncertain significance Hereditary sensory neuropathy type IE 2018-08-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 114 of the DNMT1 protein (p.Arg114Lys). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with DNMT1-related disease. ClinVar contains an entry for this variant (Variation ID: 246305). 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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