ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs375225009
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Total submissions: 4
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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-deafness-dementia syndrome 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1398 of the DNMT1 protein (p.Ser1398Leu). This variant is present in population databases (rs375225009, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of cerebellar ataxia, deafness, and narcolepsy (PMID: 35640668). ClinVar contains an entry for this variant (Variation ID: 618605). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNMT1 protein function with a negative predictive value of 80%. 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.
GeneDx RCV000757171 SCV001778662 uncertain significance not provided 2023-09-29 criteria provided, single submitter clinical testing Reported in a family with hearing loss in published literature (Pan et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35640668)
Ambry Genetics RCV002332537 SCV002630193 likely benign Inborn genetic diseases 2020-03-19 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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