Submissions for variant NM_006892.4(DNMT3B):c.1337T>C (p.Phe446Ser)

dbSNP: rs150736372

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000985130	SCV001301558	uncertain significance	Immunodeficiency-centromeric instability-facial anomalies syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244027	SCV001417219	uncertain significance	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency	2022-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 446 of the DNMT3B protein (p.Phe446Ser). This variant is present in population databases (rs150736372, gnomAD 0.1%). This missense change has been observed in individual(s) with immunodeficiency-centromeric instability-facial anomalies syndrome (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 800927). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489986	SCV004241857	uncertain significance	not specified	2023-12-05	criteria provided, single submitter	clinical testing	Variant summary: DNMT3B c.1337T>C (p.Phe446Ser) results in a non-conservative amino acid change located in the DNMT3, cysteine rich ADD domain, GATA1-like zinc finger domain (IPR040552) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DNMT3B causing ICF Syndrome, Type 1 (0.00014 vs 0.0011), allowing no conclusion about variant significance. c.1337T>C has been reported in the literature in at least one homozygous individual with a diagnosis of ICF Syndrome (e.g. Alfares_2017). However, this report does not provide unequivocal conclusions about association of the variant with ICF Syndrome, Type 1 due to the uncertainty caused by elevated consanguinity within the study population. 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: 28454995). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One classified the variant as likely pathogenic, and two classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000985130	SCV005442217	uncertain significance	Immunodeficiency-centromeric instability-facial anomalies syndrome 1	2024-12-19	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985130	SCV001133116	likely pathogenic	Immunodeficiency-centromeric instability-facial anomalies syndrome 1	2019-09-26	no assertion criteria provided	clinical testing