Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001553497 | SCV001774377 | likely pathogenic | not provided | 2022-12-15 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27721487, 27928732, 33692849, 36455200, 35781188, 33585199, 36322930, 36112138, 25920683) |
Genetic Services Laboratory, |
RCV001553497 | SCV002068774 | likely pathogenic | not provided | 2021-10-05 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.1187T>C, in exon 11 that results in an amino acid change, p.Ile396Thr. This sequence change has been described in the gnomAD database with frequency of 0.006% in the African American/African subpopulation (dbSNP rs747072227). The p.Ile396Thr change affects a moderately conserved amino acid residue located in the DEAD domain of the DDX41 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile396Thr substitution. This sequence change has been described in identical twin brothers with a personal history of myelodysplastic syndrome (MDS) and family history of acute myeloid leukemia along with a recurrent somatic mutation in DDX41 (PMID: 25920683) and in a woman with MDS and history of ovarian cancer (PMID: 33585199). Collectively, these evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively. |
Invitae | RCV001553497 | SCV003300455 | likely pathogenic | not provided | 2023-09-25 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 396 of the DDX41 protein (p.Ile396Thr). This variant is present in population databases (rs747072227, gnomAD 0.007%). This missense change has been observed in individuals with leukemia and/or myelodysplastic syndrome (PMID: 25920683, 33585199, 36322930; Invitae). ClinVar contains an entry for this variant (Variation ID: 224635). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
OMIM | RCV000210262 | SCV000266345 | risk factor | DDX41-related hematologic malignancy predisposition syndrome | 2023-03-16 | no assertion criteria provided | literature only |