Submissions for variant NM_016222.4(DDX41):c.766G>A (p.Glu256Lys)

gnomAD frequency: 0.00002  dbSNP: rs746011550

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001822651	SCV002071825	uncertain significance	not specified	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change has been previously described in at least one individual with myeloid neoplasms but no additional information was provided (PMID: 28637623). This sequence change has been described in the gnomAD database with a low population frequency of 0.0016% (dbSNP rs746011550). The p.Glu256Lys change affects a highly conserved amino acid residue located in a domain of the DDX41 protein that is known to be functional. The p.Glu256Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu256Lys change remains unknown at this time.
GeneDx	RCV004591586	SCV005079073	likely pathogenic	not provided	2024-07-12	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; Observed in the germline of individuals with DDX41-related hematologic disease or malignancy, as well as healthy controls in a case-control study (PMID: 36322930); This variant is associated with the following publications: (PMID: 27721487, 37506341, 28637623, 36322930)
Labcorp Genetics (formerly Invitae), Labcorp	RCV004591586	SCV005812729	uncertain significance	not provided	2024-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 256 of the DDX41 protein (p.Glu256Lys). This variant is present in population databases (rs746011550, gnomAD 0.006%). This missense change has been observed in individual(s) with myelodysplastic syndrome and/or myeloid neoplasm (PMID: 36322930, 37199125). ClinVar contains an entry for this variant (Variation ID: 1338053). 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 disruptive. 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.
Ambry Genetics	RCV005320882	SCV005985629	uncertain significance	Inborn genetic diseases	2025-02-20	criteria provided, single submitter	clinical testing	The p.E256K variant (also known as c.766G>A), located in coding exon 8 of the DDX41 gene, results from a G to A substitution at nucleotide position 766. The glutamic acid at codon 256 is replaced by lysine, an amino acid with similar properties. This variant was reported in individual(s) with hematologic malignancy; however germline status was not definitively confirmed (Makishima H et al. Blood, 2023 Feb;141:534-549; Badar T et al. Haematologica, 2023 Nov;108:3033-3043). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004731184	SCV005340234	uncertain significance	DDX41-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The DDX41 c.766G>A variant is predicted to result in the amino acid substitution p.Glu256Lys. To our knowledge, this variant has not been reported in association with DDX41-related hereditary disorders. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as a variant of uncertain significance or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1338053/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.