ClinVar Miner

Submissions for variant NM_022552.5(DNMT3A):c.2141C>G (p.Ser714Cys)

gnomAD frequency: 0.00002  dbSNP: rs367909007
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000658860 SCV000780657 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV001251185 SCV001426543 likely pathogenic Tatton-Brown-Rahman overgrowth syndrome criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001251185 SCV004292063 uncertain significance Tatton-Brown-Rahman overgrowth syndrome 2023-09-30 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 714 of the DNMT3A protein (p.Ser714Cys). 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 clinical features of Tatton-Brown-Rahman syndrome (PMID: 28475857, 32860008). ClinVar contains an entry for this variant (Variation ID: 546858). 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. Experimental studies have shown that this missense change affects DNMT3A function (PMID: 30705090, 31861499). 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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