ClinVar Miner

Submissions for variant NM_022552.5(DNMT3A):c.2207G>A (p.Arg736His)

gnomAD frequency: 0.00003  dbSNP: rs139293773
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001557227 SCV001778948 pathogenic not provided 2022-08-11 criteria provided, single submitter clinical testing Published functional studies suggest a damaging effect: disruption of catalytic activity of DNMT3a (Khrabrova et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27771989, 33648567, 22077061, 25964253, 22722925, 25650308, 30705090, 29900417, 32442302, 31861499, 31685998, 33087320, 34166485, 35771960, 35671390, 35556126, 34587239)
Genologica Medica RCV003227525 SCV003923340 pathogenic Tatton-Brown-Rahman overgrowth syndrome criteria provided, single submitter clinical testing
Invitae RCV003227525 SCV004316779 uncertain significance Tatton-Brown-Rahman overgrowth syndrome 2023-09-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 736 of the DNMT3A protein (p.Arg736His). 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 missense change has been observed in individual(s) with acute myeloid leukemia and clinical features of DNMT3A-related disorders and/or Tatton-Brown-Rahman syndrome (PMID: 25650308, 29900417, 31685998, 34315901). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1194481). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DNMT3A function (PMID: 22722925, 31861499, 36528185). This variant disrupts the p.Arg736 amino acid residue in DNMT3A. Other variant(s) that disrupt this residue have been observed in individuals with DNMT3A-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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.

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