Submissions for variant NM_016222.4(DDX41):c.465G>A (p.Met155Ile)

gnomAD frequency: 0.00031  dbSNP: rs199697328

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001658800	SCV001873912	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	Observed in the presumed germline of individuals with myeloid disorders or malignancies who lacked a second somatic DDX41 variant (PMID: 33929502, 25920683, 37199125, 35671390, 35443031, 37154083, 37434984, 37874914); Published functional studies demonstrate slightly reduced cellular growth and cell cycle arrest similar to wildtype (PMID: 37434984); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26712909, 27928732, 28547672, 27502187, 33692849, 33585199, 25920683, 33929502, 35671390, 37199125, 36672294, 37434984, 37874914, 37506341, 35443031, 37154083, 37665752, 38492200)
Genetic Services Laboratory, University of Chicago	RCV001821945	SCV002070595	uncertain significance	not specified	2021-09-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the DDX41 gene demonstrated a sequence change, c.465G>A, in exon 6 that results in an amino acid change, p.Met155Ile. The p.Met155Ile change has been identified in one patient with refractory anemia with excess blasts, type 1 (PMID: 25920683). This sequence change has been described in the gnomAD database with a population frequency of 0.042% in non- Finnish European populations (dbSNP rs199697328). The p.Met155Ile change affects a highly conserved amino acid residue located in a domain of the DDX41 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met155Ile substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met155Ile change remains unknown at this time.
Mendelics	RCV001821945	SCV002519085	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477874	SCV002777655	uncertain significance	DDX41-related hematologic malignancy predisposition syndrome	2021-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001658800	SCV003278546	uncertain significance	not provided	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 155 of the DDX41 protein (p.Met155Ile). This variant is present in population databases (rs199697328, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with myelodysplastic syndromes (PMID: 25920683, 35671390). ClinVar contains an entry for this variant (Variation ID: 1254618). 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 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	RCV002477874	SCV004190936	uncertain significance	DDX41-related hematologic malignancy predisposition syndrome	2024-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004980621	SCV005563847	uncertain significance	Inborn genetic diseases	2024-10-29	criteria provided, single submitter	clinical testing	The p.M155I variant (also known as c.465G>A), located in coding exon 6 of the DDX41 gene, results from a G to A substitution at nucleotide position 465. The methionine at codon 155 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been detected in numerous individuals with a suspected or confirmed myeloid neoplasm (Polprasert C et al. Cancer Cell 2015 May;27(5):658-70; Goyal T et al. Am J Clin Pathol 2021 Oct;156(5):829-838; Tierens A et al. Front Oncol 2023 Jun;13:1153082; Jelloul FZ et al. Am J Hematol 2023 Aug;98(8):E193-E196; Badar T et al. Haematologica 2023 Nov;108(11):3033-3043).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004752033	SCV005352867	uncertain significance	DDX41-related disorder	2024-05-05	no assertion criteria provided	clinical testing	The DDX41 c.465G>A variant is predicted to result in the amino acid substitution p.Met155Ile. This variant was reported in a patient with refractory anemia with excess blasts, along with an abnormal karyotype involving chromosome 20q11.2 deletion in 17 cells (Table 1; Polprasert et al. 2015. PubMed ID: 25920683). This variant was also reported in an individual with chronic myeloid leukemia (Goyal et al 2021. PubMed ID: 33929502, Table 1) and an individual with acute myeloid leukemia (Bannon et al 2020. PubMed ID: 33585199, Table S1). This variant is reported in 0.042% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1254618/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.