ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.919A>G (p.Lys307Glu) (rs148831705)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216984 SCV000279684 uncertain significance not provided 2015-12-31 criteria provided, single submitter clinical testing The K307E variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. It was not observed with any significant frequency in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project. The K307Evariant is a non-conservative amino acid substitution, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties. However, thissubstitution occurs at a position where amino acids with similar properties to Lysine are toleratedacross species, and in silico analysis predicts this variant likely does not alter the proteinstructure/function. Therefore, based on the currently available information, it is unclear whether thisvariant is a pathogenic variant or a rare benign variant.
Invitae RCV000536816 SCV000651327 uncertain significance Hereditary sensory neuropathy type IE 2017-09-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 307 of the DNMT1 protein (p.Lys307Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs148831705, ExAC 0.01%). This variant has not been reported in the literature in individuals with DNMT1-related disease. ClinVar contains an entry for this variant (Variation ID: 234681). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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