VCV000224634.10 - ClinVar

NM_016222.4(DDX41):c.1574G>A (p.Arg525His)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016222.4(DDX41):c.1574G>A (p.Arg525His)

Variation ID: 224634 Accession: VCV000224634.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q35.3 5: 177512369 (GRCh38) [ NCBI UCSC ] 5: 176939370 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 27, 2016	Feb 14, 2024	Jun 28, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_016222.4:c.1574G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_057306.2:p.Arg525His	missense
NM_001321732.2:c.1196G>A	NP_001308661.1:p.Arg399His	missense
NM_001321830.2:c.1196G>A	NP_001308759.1:p.Arg399His	missense
NM_016222.3:c.1574G>A
NC_000005.10:g.177512369C>T
NC_000005.9:g.176939370C>T
NG_046846.2:g.9593G>A
LRG_1386:g.9593G>A
LRG_1386t1:c.1574G>A	LRG_1386p1:p.Arg525His
	Q9UJV9:p.Arg525His

... more HGVS ... less HGVS

Protein change

R525H, R399H

Other names

Canonical SPDI

NC_000005.10:177512368:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA358659 UniProtKB: Q9UJV9#VAR_076362 OMIM: 608170.0002 dbSNP: rs869312828 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DDX41		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	581	649

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
DDX41-related hematologic malignancy predisposition syndrome	Pathogenic; risk factor (3)	no assertion criteria provided	Mar 16, 2023	RCV000210250.7
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jun 28, 2022	RCV002288840.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002578413.2 First in ClinVar: Oct 15, 2022 Last updated: Mar 04, 2023	Comment: 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; … (more) 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; Published functional studies are inconclusive, some suggesting that this variant by itself does not significantly affect protein translation or localization, some suggesting a possible hypomorphic effect, and some suggesting inhibition of proliferation and ATPase activity (Kadono et al., 2016; Lewinsohn et al., 2016; Chlon et al., 2021); Observed in the germline of an individual with myelodysplastic syndrome in published literature (Lewinsohn et al., 2016); Common second hit somatic variant observed in many affected individuals who also have a DDX41 germline variant (Polprasert et al., 2015); This variant is associated with the following publications: (PMID: 26712909, 34473945, 31713024, 34349893, 27174803, 33929502, 33836623, 33585199, 33692849, 27721487, 25920683) (less)
Uncertain significance (Jun 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003439299.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 25920683‚ 27174803‚ 26712909 Comment: Experimental studies have shown that this missense change affects DDX41 function (PMID: 25920683, 27174803). Algorithms developed to predict the effect of missense changes on protein … (more) Experimental studies have shown that this missense change affects DDX41 function (PMID: 25920683, 27174803). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 224634). This missense change has been observed in individual(s) with leukemia (PMID: 26712909). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 525 of the DDX41 protein (p.Arg525His). 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. (less)
risk factor (Mar 16, 2023)	no assertion criteria provided Method: literature only	MYELOPROLIFERATIVE/LYMPHOPROLIFERATIVE NEOPLASMS, FAMILIAL (MULTIPLE TYPES), SUSCEPTIBILITY TO Affected status: not provided Allele origin: unknown	OMIM Accession: SCV000266344.2 First in ClinVar: Mar 27, 2016 Last updated: Mar 26, 2023	Publications: PubMed (2) PubMed: 26712909‚ 25920683 Comment on evidence: In 3 members of a family (CCB 31379) with MPLPF, Lewinsohn et al. (2016) identified a heterozygous germline c.1574G-A transition (c.1574G-A, NM_016222.2) in the DDX41 … (more) In 3 members of a family (CCB 31379) with MPLPF, Lewinsohn et al. (2016) identified a heterozygous germline c.1574G-A transition (c.1574G-A, NM_016222.2) in the DDX41 gene, resulting in an arg525-to-his (R525H) substitution. The patients were diagnosed between 44 and 56 years of age. For discussion of the somatic c.1574G-A transition in the DDX41 gene, resulting in an arg525-to-his (R525H) substitution at a conserved residue in an ATP binding domain, that was found in compound heterozygous state in individuals with multiple types of familial myeloproliferative/lymphoproliferative neoplasms (MPLPF; 616871) by Polprasert et al. (2015), see (608170.0001). Polprasert et al. (2015) found a heterozygous somatic R525X mutation in 6 of 1,034 unrelated patients with sporadic occurrence of MDS/AML. One of these patients carried a germline Asp140fs (608170.0001) on the other allele and another had a germline deletion of 5q including the DDX41 gene (see also 153550). In vitro functional expression studies indicated that the R525H mutation interfered with the ability of DDX41 to interact with several major spliceosomal components. Polprasert et al. (2015) concluded that it was a hypomorphic allele. (less)
Pathogenic (Feb 17, 2022)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	DDX41-related hematologic malignancy predisposition syndrome Affected status: yes Allele origin: germline	Clinical Genomics Labs, University Health Network Accession: SCV003920866.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023
not provided (-)	no classification provided Method: literature only	DDX41-related hematologic malignancy predisposition syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001999939.2 First in ClinVar: Nov 06, 2021 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 27174803‚ 26712909‚ 28547672 Comment: Most common somatic variant; also reported in the germline [Kadono et al 2016, Lewinsohn et al 2016, Cheah et al 2017]

Comment:

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; Published functional studies are inconclusive, some suggesting that this variant by itself does not significantly affect protein translation or localization, some suggesting a possible hypomorphic effect, and some suggesting inhibition of proliferation and ATPase activity (Kadono et al., 2016; Lewinsohn et al., 2016; Chlon et al., 2021); Observed in the germline of an individual with myelodysplastic syndrome in published literature (Lewinsohn et al., 2016); Common second hit somatic variant observed in many affected individuals who also have a DDX41 germline variant (Polprasert et al., 2015); This variant is associated with the following publications: (PMID: 26712909, 34473945, 31713024, 34349893, 27174803, 33929502, 33836623, 33585199, 33692849, 27721487, 25920683)

Comment:

Experimental studies have shown that this missense change affects DDX41 function (PMID: 25920683, 27174803). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 224634). This missense change has been observed in individual(s) with leukemia (PMID: 26712909). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 525 of the DDX41 protein (p.Arg525His). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Myeloid neoplasms with germline DDX41 mutation.	Cheah JJC	International journal of hematology	2017	PMID: 28547672
Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.	Kadono M	Experimental hematology	2016	PMID: 27174803
Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.	Lewinsohn M	Blood	2016	PMID: 26712909
Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms.	Polprasert C	Cancer cell	2015	PMID: 25920683

Text-mined citations for rs869312828 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_016222.4(DDX41):c.1574G>A (p.Arg525His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs869312828 ...