Submissions for variant NM_016222.4(DDX41):c.490C>T (p.Arg164Trp)

gnomAD frequency: 0.00017  dbSNP: rs142143752

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001818508	SCV002069930	likely pathogenic	not provided	2021-09-29	criteria provided, single submitter	clinical testing	DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.490C>T, in exon 6 that results in an amino acid change, p.Arg164Trp. This sequence change has been described in the gnomAD database with a frequency of 0.16% in Ashkenazi Jewish populations (dbSNP rs142143752). The p.Arg164Trp change has been identified segregating with lymphoid malignancies in five individuals from one family (PMID: 26712909). This variant has also been seen in a second family where it segregates with lymphoid malignancies (verbal communication). The p.Arg164Trp change affects a highly conserved amino acid residue located adjacent to the Q motif, a region involved in adenosine triphosphate binding and hydrolysis, and thought to be important for regulating DDX41 helicase activity. The majority of in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide results for the p.Arg164Trp substitution that suggest it be pathogenic. Functional studies demonstrate that the p.Arg164Trp change does not overtly affect protein translation or localization (PMID: 26712909); however, the impact on protein activity or binding ability has not been determined. These collective evidences indicate this this sequence change is likely pathogenic.
GeneDx	RCV001818508	SCV002567410	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in unrelated individuals with lymphoma (Li et al., 2022); Published functional studies demonstrate that this variant does not impact nuclear localization (Lewinsohn et al., 2016); This variant is associated with the following publications: (PMID: 28547672, 26917736, 27819178, 27928732, 28637623, 26712909, 35781188, 35671390)
Invitae	RCV001818508	SCV003439312	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the DDX41 protein (p.Arg164Trp). This variant is present in population databases (rs142143752, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lymphoma and/or multiple myeloma (PMID: 26712909, 35671390). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224638). 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. Studies have shown that this missense change does not significantly alter or has an unclear effect on DDX41 gene expression (PMID: 26712909). 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.
Baylor Genetics	RCV000210264	SCV004190927	uncertain significance	DDX41-related hematologic malignancy predisposition syndrome	2023-10-30	criteria provided, single submitter	clinical testing
OMIM	RCV000210264	SCV000266348	risk factor	DDX41-related hematologic malignancy predisposition syndrome	2023-03-16	no assertion criteria provided	literature only