Submissions for variant NM_006892.4(DNMT3B):c.2441A>G (p.His814Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281886	SCV002572463	likely pathogenic	Immunodeficiency-centromeric instability-facial anomalies syndrome 1	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: DNMT3B c.2441A>G (p.His814Arg) 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 was absent in 251160 control chromosomes (gnomAD). c.2441A>G has been reported in the literature in at least two compound heterozygous individuals affected with ICF Syndrome (e.g. Wijmenga_2000, Jiang_2005). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Xie_2006, Moarefi_2011). The most pronounced effect of the variant results in approximately 2% methylation activity compared to the wild-type protein and disrupted homo-oligomerization and a severely impacted ability to bind SAM (Moarefi_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003594182	SCV004298053	likely pathogenic	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 814 of the DNMT3B protein (p.His814Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome (PMID: 11102980, 15580563). This variant is also known as c.2417A>G, p.His806Arg. ClinVar contains an entry for this variant (Variation ID: 1705256). 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 expected to disrupt DNMT3B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT3B function (PMID: 16543361, 21549127). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.