ClinVar Miner

Submissions for variant NM_022552.4(DNMT3A):c.2645G>A (p.Arg882His) (rs147001633)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485343 SCV000566073 pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing The R882H variant in the DNMT3A gene has been reported as a germline variant in a 6-year-old female patient with Tatton-Brown–Rahman overgrowth syndrome (TBRS) (Kosaki et al., 2017). The R882 codon has also been reported as a hot spot location for somatic mutations in individuals with acute myeloid leukemia (AML), and R882H is thought to contribute to leukemogenesis by increasing CDK1 protein levels and enhancing cell-cycle activity (Xu et al., 2014). Functional studies indicate that HEK293T cells expressing the R882H variant have severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014). The R882H variant is not observed in large population cohorts (Lek et al., 2016). The R882H variant is a conservative amino acid substitution. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. A missense variant in the same residue (R882C) has been reported previously as a somatic variant in individuals with AML and refractory anemia with excess blasts (Ewalt et al., 2011), as well as a germline variant in an 18-year-old male patient with TBRS who developed AML at age 15 (Hollink et al., 2017). We interpret R882H as a pathogenic variant.
Invitae RCV000524775 SCV000655299 uncertain significance Tatton-Brown-rahman syndrome 2017-09-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 882 of the DNMT3A protein (p.Arg882His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs147001633, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with Tatton-Brown-Rahman overgrowth syndrome (PMID: 27991732). ClinVar contains an entry for this variant (Variation ID: 375881). Experimental studies have shown that this missense change severely impairs tetramerization and DNA methyltransferase activity in vitro (PMID: 24656771). This variant also disrupts dimerization and shows a 2-fold reduction in enzyme processivity (PMID: 22722925). Finally, in experiments with bone marrow transplantation, expression of this variant combined with Tet2 inactivation led to the development of leukemias, a result that is consistent with recurrent observation of this variant in acute myeloid leukemia (PMID: 26876596, 24622842). In summary, this variant has uncertain impact on DNMT3A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000623601 SCV000740689 pathogenic Inborn genetic diseases 2017-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: SUSPECTED CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected
Database of Curated Mutations (DoCM) RCV000430182 SCV000503760 pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437399 SCV000503761 likely pathogenic Myelodysplastic syndrome 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418424 SCV000503762 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
OMIM RCV000524775 SCV000700192 pathogenic Tatton-Brown-rahman syndrome 2018-05-08 no assertion criteria provided literature only
OMIM RCV000430182 SCV000700193 pathogenic Acute myeloid leukemia 2018-05-08 no assertion criteria provided literature only

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