Submissions for variant NM_006892.4(DNMT3B):c.73G>A (p.Gly25Arg)

gnomAD frequency: 0.00079  dbSNP: rs151128145

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201367	SCV000758126	likely benign	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	2025-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000762341	SCV000892649	uncertain significance	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000636686	SCV001301439	uncertain significance	Immunodeficiency-centromeric instability-facial anomalies syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002529854	SCV003526595	uncertain significance	Inborn genetic diseases	2022-01-10	criteria provided, single submitter	clinical testing	The c.73G>A (p.G25R) alteration is located in exon 2 (coding exon 1) of the DNMT3B gene. This alteration results from a G to A substitution at nucleotide position 73, causing the glycine (G) at amino acid position 25 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768489	SCV005380556	likely benign	not specified	2024-08-19	criteria provided, single submitter	clinical testing	Variant summary: DNMT3B c.73G>A (p.Gly25Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 1613942 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DNMT3B causing ICF Syndrome, Type 1 phenotype (0.0011). c.73G>A has been reported in the literature in a heterozygous individual affected with malignant Hodgkin lymphoma, B cell deficiency without evidence of causality (e.g. Rudilla_2019). This report does not provide unequivocal conclusions about association of the variant with ICF Syndrome, Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31681265). ClinVar contains an entry for this variant (Variation ID: 530703). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000762341	SCV001743643	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000762341	SCV001968332	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004731002	SCV005338484	uncertain significance	DNMT3B-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The DNMT3B c.73G>A variant is predicted to result in the amino acid substitution p.Gly25Arg. This variant was reported in an individual with Hirschsprung disease (Torroglosa et al 2014. PubMed ID: 24577265). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.