Submissions for variant NM_022552.5(DNMT3A):c.250G>A (p.Ala84Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002612626	SCV003513180	uncertain significance	Tatton-Brown-Rahman overgrowth syndrome	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 84 of the DNMT3A protein (p.Ala84Thr). This variant is present in population databases (rs753287419, gnomAD 0.007%). 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: 2194901). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNMT3A protein function with a negative predictive value of 95%. 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.
PreventionGenetics, part of Exact Sciences	RCV004747221	SCV005349874	uncertain significance	DNMT3A-related disorder	2024-04-23	no assertion criteria provided	clinical testing	The DNMT3A c.250G>A variant is predicted to result in the amino acid substitution p.Ala84Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0063% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.