Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001201371 | SCV000634187 | pathogenic | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 764 of the DNMT3B protein (p.Arg764Ser). This variant is present in population databases (rs759448571, gnomAD 0.003%). This missense change has been observed in individual(s) with centromeric instability and facial anomalies (ICF) syndrome (PMID: 17893117, 23486536; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg756Ser. ClinVar contains an entry for this variant (Variation ID: 461482). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Illumina Laboratory Services, |
RCV000544568 | SCV000914951 | uncertain significance | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 | 2017-04-28 | criteria provided, single submitter | clinical testing | The DNMT3B c.2292G>T (p.Arg764Ser) variant has been reported in a compound heterozygous state with a frameshift variant in one patient with immunodeficiency-centromeric instability-facial anomalies syndrome (Hagleitner et al. 2008; Weemaes et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional data using isolated T-lymphocytes from the patient carrying the p.Arg764Ser variant show that the T-cell expansion was significantly reduced compared to unrelated controls (Weemaes et al. 2013). The evidence for this variant is limited. The p.Arg764Ser variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for immunodeficiency-centromeric instability-facial anomalies syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |