ClinVar Miner

Submissions for variant NM_022552.5(DNMT3A):c.1385C>T (p.Ala462Val)

gnomAD frequency: 0.00027  dbSNP: rs200845575
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001819492 SCV002068531 likely benign not specified 2019-01-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002542576 SCV003257000 uncertain significance Tatton-Brown-Rahman overgrowth syndrome 2024-05-14 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 462 of the DNMT3A protein (p.Ala462Val). This variant is present in population databases (rs200845575, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNMT3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1337006). 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 DNMT3A 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.
PreventionGenetics, part of Exact Sciences RCV003968578 SCV004792034 uncertain significance DNMT3A-related disorder 2023-10-31 no assertion criteria provided clinical testing The DNMT3A c.1385C>T variant is predicted to result in the amino acid substitution p.Ala462Val. This variant was reported in a sample from a central nervous system tumor in a patient with a cancer of unknown primary origin (Bakow et al. 2020. PubMed ID: 32310333). This variant is reported in 0.072% of alleles in individuals of European (Finnish) descent in gnomAD, which might be too common to be a primary cause of autosomal dominant disease (http://gnomad.broadinstitute.org/variant/2-25469073-G-A). While we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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