ClinVar Miner

Submissions for variant NM_022552.5(DNMT3A):c.2206C>T (p.Arg736Cys)

gnomAD frequency: 0.00002  dbSNP: rs761934754
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostic Laboratory, Strasbourg University Hospital RCV001260610 SCV001437702 likely pathogenic Intellectual disability 2020-09-10 criteria provided, single submitter clinical testing
Invitae RCV001340498 SCV001534312 uncertain significance Tatton-Brown-Rahman overgrowth syndrome 2022-08-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 736 of the DNMT3A protein (p.Arg736Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 981259). 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"). 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.
GeneDx RCV003319458 SCV004023467 pathogenic not provided 2023-08-14 criteria provided, single submitter clinical testing Published functional studies demonstrate protein instability and decreased activity (Huang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28533481, 25964253, 32533252, 33101740, 32761230, 32442302, 34429321, 36912186)

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