ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.4193C>T (p.Ser1398Leu) (rs375225009)

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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 RCV000757171 SCV000885306 uncertain significance not provided 2018-04-12 criteria provided, single submitter clinical testing The DNMT1: p.Ser1398Leu variant (rs375225009) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the Latino population (identified on 10 out of 34,154 chromosomes). The serine at position 1398 is moderately conserved considering 12 species (Alamut v2.11) and computational analyses of the p.Ser1398Leu variant on protein structure and function indicate a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ser1398Leu variant with certainty.
Invitae RCV000795227 SCV000934674 uncertain significance Hereditary sensory neuropathy type IE 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1398 of the DNMT1 protein (p.Ser1398Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs375225009, ExAC 0.03%). This variant has not been reported in the literature in individuals with DNMT1-related disease. 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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