Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Mendelics | RCV000990298 | SCV001141231 | pathogenic | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000990298 | SCV002819611 | likely pathogenic | Immunodeficiency-centromeric instability-facial anomalies syndrome 1 | 2022-12-16 | criteria provided, single submitter | clinical testing | Variant summary: DNMT3B c.2476C>T (p.Arg826Cys) 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 allele was found at a frequency of 8e-06 in 251400 control chromosomes. c.2476C>T has been reported in the literature in individuals affected with ICF Syndrome and inborn errors of immunity (Hagleitner_2008, Velasco_2014, Simon_2020), and one of these patients was reported as compound heterozygous with a likely pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Invitae | RCV002550616 | SCV003443370 | uncertain significance | Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency | 2022-07-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 826 of the DNMT3B protein (p.Arg826Cys). This variant is present in population databases (rs201579632, gnomAD 0.004%). This missense change has been observed in individual(s) with immunodeficiency-centromeric instability-facial anomalies syndrome (PMID: 17893117). ClinVar contains an entry for this variant (Variation ID: 803606). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |