ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.1535C>T (p.Ala512Val)

dbSNP: rs1064796687
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480106 SCV000573651 uncertain significance not provided 2017-03-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DNMT1 gene. The A512V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A512V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A512V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. However, missense variants in nearby residues (P507R, P507L, Y511H, Y511C) have been reported in the Human Gene Mutation Database in association with DNMT1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV002525954 SCV003467341 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2022-06-07 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 512 of the DNMT1 protein (p.Ala512Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423895). 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: "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.
Ambry Genetics RCV003352891 SCV004081862 uncertain significance Inborn genetic diseases 2023-08-24 criteria provided, single submitter clinical testing The c.1487C>T (p.A496V) alteration is located in exon 19 (coding exon 19) of the DNMT1 gene. This alteration results from a C to T substitution at nucleotide position 1487, causing the alanine (A) at amino acid position 496 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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