ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.2836G>A (p.Gly946Ser) (rs777416084)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521081 SCV000618673 uncertain significance not provided 2017-07-06 criteria provided, single submitter clinical testing The G946S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G946S variant is observed in 2/10400 (0.02%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G946S 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, this variant has been observed at GeneDx in an individual who had a different genetic etiology for the phenotype. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000687016 SCV000814565 uncertain significance Hereditary sensory neuropathy type IE 2018-04-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 946 of the DNMT1 protein (p.Gly946Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs777416084, ExAC 0.02%). This variant has not been reported in the literature in individuals with DNMT1-related disease. ClinVar contains an entry for this variant (Variation ID: 450129). 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: "Possibly Damaging"; 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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