ClinVar Miner

Submissions for variant NM_022552.5(DNMT3A):c.1684T>C (p.Cys562Arg)

dbSNP: rs1057520788
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439792 SCV000517444 likely pathogenic not provided 2016-10-05 criteria provided, single submitter clinical testing The C562R variant in the DNMT3A gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The C562R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C562R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C562R as likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000536842 SCV000655297 uncertain significance Tatton-Brown-Rahman overgrowth syndrome 2019-04-03 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in an individual with clinical features of Tatton-Brown-Rahman syndrome (PMID: 29900417). ClinVar contains an entry for this variant (Variation ID: 379924). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 562 of the DNMT3A protein (p.Cys562Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.

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