Submissions for variant NM_006892.4(DNMT3B):c.1753G>A (p.Ala585Thr)

dbSNP: rs750849178

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001953938	SCV002246631	uncertain significance	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	2024-10-28	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 585 of the DNMT3B protein (p.Ala585Thr). 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 immunodeficiency-centromeric instability-facial anomalies syndrome and/or primary immunodeficiency (PMID: 27734333, 32135276). This variant is also known as p.A577T. ClinVar contains an entry for this variant (Variation ID: 1461133). 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 expected to disrupt DNMT3B protein function with a positive predictive value of 95%. This variant disrupts the p.Ala585 amino acid residue in DNMT3B. Other variant(s) that disrupt this residue have been observed in individuals with DNMT3B-related conditions (PMID: 11102980), 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690201	SCV005185885	uncertain significance	not specified	2024-05-04	criteria provided, single submitter	clinical testing	Variant summary: DNMT3B c.1753G>A (p.Ala585Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247888 control chromosomes. c.1753G>A has been reported in the literature in homozygous individuals affected with ICF Syndrome or a suspected primary immunodeficiency (e.g. Rechavi_2016, Simon_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27734333, 32135276). ClinVar contains an entry for this variant (Variation ID: 1461133). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.