ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.803C>T (p.Pro268Leu)

gnomAD frequency: 0.00001  dbSNP: rs779634956
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000686192 SCV000813697 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2023-07-29 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 268 of the DNMT1 protein (p.Pro268Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 566392). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. This variant is present in population databases (rs779634956, gnomAD 0.003%).
GeneDx RCV001756156 SCV001997429 uncertain significance not provided 2020-01-02 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002388197 SCV002670877 likely benign Inborn genetic diseases 2021-10-05 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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