Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002234880 | SCV000954886 | pathogenic | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency | 2023-07-14 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln783Argfs*21) in the DNMT3B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 71 amino acid(s) of the DNMT3B protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DNMT3B-related conditions. ClinVar contains an entry for this variant (Variation ID: 657788). This variant disrupts a region of the DNMT3B protein in which other variant(s) (p.Asp817Gly) have been determined to be pathogenic (PMID: 10647011, 11919202, 16501171, 26851945). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| ARUP Laboratories, |
RCV000814474 | SCV002050157 | likely pathogenic | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 | 2021-09-13 | criteria provided, single submitter | clinical testing | The DNMT3B c.2348_2349delAG; p.Gln783ArgfsTer21 variant (rs1368779496), to our knowledge, is not reported in the medical literature but is reported as likely pathogenic in ClinVar (Variation ID: 657788). This variant is found on a single chromosome in the Genome Aggregation Database (1/251464 alleles), indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Other truncating variants, as well as missense variants downstream of this frameshift variant, have been reported in individuals affected with immunodeficiency, centromeric instability and facial dysmorphism (ICF) syndrome (Hagleitner 2008, Xu 1999). Based on available information, the p.Gln783ArgfsTer21 variant is considered to be likely pathogenic. References: Hagleitner et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet. 2008 Feb;45(2):93-9. PMID: 17893117. Xu et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999 Nov 11;402(6758):187-91. PMID: 10647011. |