ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.3353A>G (p.His1118Arg) (rs150331990)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235537 SCV000293333 uncertain significance not provided 2015-11-20 criteria provided, single submitter clinical testing The H1118R 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 approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved in mammals; however, it is predicted to be outside of the targeting sequence domain of the DNMT1 protein. Additionally, the H1118R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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 RCV000824537 SCV000965438 uncertain significance Hereditary sensory neuropathy type IE 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1118 of the DNMT1 protein (p.His1118Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs150331990, ExAC 0.002%). This variant has not been reported in the literature in individuals with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 246040). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Genetics and Molecular Pathology Laboratory,Hudson Institute of Medical Research RCV000625704 SCV000599435 uncertain significance Beckwith-Wiedemann syndrome no assertion criteria provided research This variant was identified in heterozygous form in 1 of 53 cases with Beckwith Wiedemann syndrome with loss of KCNQ1OT1 at Imprinting centre 2 on 11p15.5. The variant frequency in dbSNP is 0.00001.

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