ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.4001C>T (p.Ala1334Val)

gnomAD frequency: 0.00001  dbSNP: rs766051225
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236975 SCV000293109 uncertain significance not provided 2019-09-11 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Invitae RCV001857804 SCV002125446 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2023-01-08 criteria provided, single submitter clinical testing 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. 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 expected to disrupt DNMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 245911). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. This variant is present in population databases (rs766051225, gnomAD 0.04%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1334 of the DNMT1 protein (p.Ala1334Val).
Fulgent Genetics, Fulgent Genetics RCV002479942 SCV002793343 uncertain significance Autosomal dominant cerebellar ataxia, deafness and narcolepsy; Hereditary sensory neuropathy-deafness-dementia syndrome 2021-11-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV003165660 SCV003887537 likely benign Inborn genetic diseases 2023-01-09 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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