ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.2092A>T (p.Ser698Cys) (rs1029809799)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000335 SCV001157062 uncertain significance not specified 2019-05-02 criteria provided, single submitter clinical testing The DNMT1 c.2092A>T, p.Ser698Cys variant (rs1029809799), to our knowledge, has not been reported in the medical literature or gene specific databases. However, a rare variant in the adjacent upstream amino acid (c.2089C>T; p.Arg697Trp) was identified in a 25 year old female with symptoms of peripheral neuropathy including loss of deep tendon reflexes, reduced sensitivity, in addition to sudden-onset muscle weakness (Vaeth 2019). The p.Ser698Cys variant is found on a single chromosome in the Genome Aggregation Database. The serine at codon 698 is highly conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, based on the available information, the clinical significance of this variant is uncertain.
Invitae RCV001208186 SCV001379561 uncertain significance Hereditary sensory neuropathy type IE 2019-10-14 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 698 of the DNMT1 protein (p.Ser698Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DNMT1-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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