Submissions for variant NM_016222.4(DDX41):c.3G>A (p.Met1Ile)

gnomAD frequency: 0.00012  dbSNP: rs141601766

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519179	SCV000617985	pathogenic	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Confirmed or presumably germline variant in individuals with DDX41-related phenotypes referred for genetic testing at GeneDx and in published literature (Quesada et al., 2019; Sbert et al., 2019; Rio-Machin et al., 2020; Bannon et al., 2021); Published functional studies suggest a damaging effect: shortened protein product that demonstrated altered cellular localization (Lewinsohn et al., 2016); This variant is associated with the following publications: (PMID: 26712909, 27795557, 27210295, 27133828, 31484648, 30963592, 32098966, 33585199, 28104920, 34671111, 33615436, 33692849)
CeGaT Center for Human Genetics Tuebingen	RCV000519179	SCV001154603	likely pathogenic	not provided	2017-11-01	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000210251	SCV001438362	pathogenic	DDX41-related hematologic malignancy predisposition syndrome	2020-10-02	criteria provided, single submitter	clinical testing	DDX41 c.3G>A has been reported in multiple families segregating myeloproliferative and lymphoproliferative neoplasms. This DDX41 variant (rs141601766) is rare (<0.1%) in a large population dataset (gnomAD: 23/276878 total alleles; 0.0083%; no homozygotes) and it has been reported in ClinVar. Functional studies of p.Met1Ile indicate that an alternate, downstream methioinine is used for initiation of translation and that the resulting protein is mislocalized because it lacks a nuclear locationization signal. We consider this variant to be pathogenic.
Illumina Laboratory Services, Illumina	RCV000210251	SCV002034839	pathogenic	DDX41-related hematologic malignancy predisposition syndrome	2021-11-18	criteria provided, single submitter	clinical testing	The DDX41 c.3G>A (p.Met1Ile) variant is predicted to disrupt the initiator codon and thus potentially may interfere with protein expression. Across a selection of the available literature, the p.Met1Ile variant has been identified in at least 16 individuals with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and was shown to segregate in at least one family (Lewinsohn et al. 2016; Sébert et al. 2019; Quesada et al. 2019; Rio-Machin et al. 2020). Control data are unavailable for this variant, which is reported at a frequency of 0.000153 in the European (non-Finnish) population of the Genome Aggregation Database version 2.1.1 and is found in a region of good sequence coverage. A second initiation codon variant is reported at the Met1 residue in a proband with AML (Sébert et al. 2019). Expression studies in HEK cells illustrate the p.Met1Ile variant exhibits altered cellular localization when compared to wildtype DDX41 (Lewinsohn et al. 2016). Based on the evidence, the p.Met1Ile variant is classified as pathogenic for DDX41-related hematologic malignancy predisposition syndrome.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000210251	SCV002049719	pathogenic	DDX41-related hematologic malignancy predisposition syndrome	2021-04-15	criteria provided, single submitter	clinical testing
Invitae	RCV000519179	SCV003299840	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the DDX41 mRNA. The next in-frame methionine is located at codon 127. This variant is present in population databases (rs141601766, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with acute myeloid leukemia, myelodysplastic syndrome and chronic myeloid leukemia (PMID: 26712909, 27133828, 27795557). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224637). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects DDX41 function (PMID: 26712909). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003907781	SCV004723001	pathogenic	DDX41-related condition	2023-12-20	criteria provided, single submitter	clinical testing	The DDX41 c.3G>A variant is predicted to disrupt the translation initiation site (Start loss). This variant was found in several families with a history of hematologic malignancies (see, for example, Lewinsohn et al. 2016. PubMed ID: 26712909; Cardoso et al. 2016. PubMed ID: 27133828; Quesada et al. 2019. PubMed ID: 30963592). The c.3G>A variant was reported primarily in patients with late onset MDS/AML, but it was also reported in at least one patient with chronic myeloid leukemia and one patient with AML and non-Hodgkin lymphoma. Biochemical studies indicate the c.3G>A substitution results in altered translation of a smaller DDX41 protein with improper cellular localization (Lewinsohn et al. 2016. PubMed ID: 26712909). This variant is reported in 0.015% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/224637/). This variant is interpreted as pathogenic.
OMIM	RCV000210251	SCV000266347	risk factor	DDX41-related hematologic malignancy predisposition syndrome	2023-03-16	no assertion criteria provided	literature only
Bone Marrow Failure laboratory, Queen Mary University London	RCV001256169	SCV001432953	pathogenic	Bone marrow hypocellularity	2020-08-28	no assertion criteria provided	research	This heterozygous start-loss variant of DDX41 was identified in a 20-year old male with pancytopenia. The following ACMG/AMP criteria were used: PVS1, PS1, PM4, PP3
Bone Marrow Failure laboratory, Queen Mary University London	RCV001256171	SCV001432955	pathogenic	Myelodysplasia	2020-08-28	no assertion criteria provided	research	This heterozygous start-loss variant of DDX41 was identified in a 41-year old female with MDS. She had inherited this variant from her father. The following ACMG/AMP criteria were used: PVS1, PS1, PM4, PP3
GeneReviews	RCV000210251	SCV001999938	not provided	DDX41-related hematologic malignancy predisposition syndrome		no assertion provided	literature only	Common recurrent germline variant, esp in persons of European ancestry [Cheah et al 2017, Quesada et al 2019, Bannon et al 2021]
Genetic Services Laboratory, University of Chicago	RCV000210251	SCV002070517	pathogenic	DDX41-related hematologic malignancy predisposition syndrome	2020-11-19	no assertion criteria provided	clinical testing	DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.3G>A, in exon 1 that affects the transcription start codon, p.Met1?. This pathogenic sequence change has previously been described in patients and families with DDX41-related hereditary myelodysplastic syndrome (MDS) and AML (PMIDs: 26712909, 27133828, 27795557). Studies have shown that the disruption of the initiating methionine resulted in a predominant smaller protein (PMID: 26712909).
Clinical Genomics Labs, University Health Network	RCV000210251	SCV003920851	uncertain significance	DDX41-related hematologic malignancy predisposition syndrome	2018-07-23	no assertion criteria provided	clinical testing