Submissions for variant NM_022552.5(DNMT3A):c.1114G>A (p.Val372Ile)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002972277	SCV003290010	uncertain significance	Tatton-Brown-Rahman overgrowth syndrome	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 372 of the DNMT3A protein (p.Val372Ile). This variant is present in population databases (rs371677904, gnomAD 0.006%). 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: 2076359). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNMT3A protein function. 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.
Ambry Genetics	RCV002979243	SCV003754973	uncertain significance	Inborn genetic diseases	2021-03-26	criteria provided, single submitter	clinical testing	The c.1114G>A (p.V372I) alteration is located in exon 9 (coding exon 8) of the DNMT3A gene. This alteration results from a G to A substitution at nucleotide position 1114, causing the valine (V) at amino acid position 372 to be replaced by an isoleucine (I). The p.V372I alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004747167	SCV005349413	uncertain significance	DNMT3A-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The DNMT3A c.1114G>A variant is predicted to result in the amino acid substitution p.Val372Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.