VCV002505168.3 - ClinVar

NM_001357.5(DHX9):c.1240G>A (p.Gly414Arg)

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.

(2)

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.

Pathogenic/Likely pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001357.5(DHX9):c.1240G>A (p.Gly414Arg)

Variation ID: 2505168 Accession: VCV002505168.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q25.3 1: 182860092 (GRCh38) [ NCBI UCSC ] 1: 182829227 (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	Jul 8, 2023	Nov 3, 2024	Oct 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001357.5:c.1240G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001348.2:p.Gly414Arg	missense
NR_033302.2:n.1509G>A		non-coding transcript variant
NC_000001.11:g.182860092G>A
NC_000001.10:g.182829227G>A
NG_029930.1:g.25789G>A
NG_029930.2:g.25747G>A

... more HGVS ... less HGVS

Protein change

G414R

Other names

Canonical SPDI

NC_000001.11:182860091:G:A

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

OMIM: 603115.0005 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.
DHX9		-	-	GRCh38 GRCh37	61	91

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.
DHX9-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jul 27, 2022	RCV003238926.1
INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 75	Pathogenic (1)	no assertion criteria provided	Oct 28, 2024	RCV004775366.1

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.
Likely pathogenic (Jul 27, 2022)	no assertion criteria provided Method: research, in vivo	DHX9-related disorder (Sporadic) Affected status: not applicable, yes Allele origin: de novo, not applicable	Center for Medical Genetics, Keio University School of Medicine Accession: SCV003930392.1 First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023	Publications: PubMed (1) PubMed: 37369308 Observation 1: Age: 0-9 years Sex: female Ethnicity/Population group: East Asian Geographic origin: Japan Observation 2: Comment on evidence: Abnormal eye development of Drosopphila when wildtype human DHX9 was ectopically expressed. Minimal effect when mutant protein was expressed. Result: Forced ectopic expression of wildtype or mutant human protein in the Drosophila embryonic eyes Observation 3: Result: Wildtype or mutant human DHX9 was ectopically expressed in developing human Drosophila eyes. When wildtype human DHX9 protein was expressed, Drosophila eyes were abnormal. When mutant DHX9 was expressed, the eyes were less abnormal.
Pathogenic (Oct 28, 2024)	no assertion criteria provided Method: literature only	INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 75 Affected status: not provided Allele origin: germline	OMIM Accession: SCV005382836.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Publications: PubMed (1) PubMed: 37369308 Comment on evidence: In an 8-year-old Japanese girl with autosomal dominant intellectual developmental disorder-75 (MRD75; 620988), Yamada et al. (2023) identified a de novo heterozygous c.1240G-A transition (c.1240G-A, … (more) In an 8-year-old Japanese girl with autosomal dominant intellectual developmental disorder-75 (MRD75; 620988), Yamada et al. (2023) identified a de novo heterozygous c.1240G-A transition (c.1240G-A, NM_001357.4) in the DHX9 gene, resulting in a gly414-to-arg (G414R) substitution at a highly conserved residue in the ATP-binding domain. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not present in 8,300 Japanese controls or public databases, including gnomAD. Studies of patient cells were not performed, but expression of the corresponding mutation in Drosophila and mice indicated that it is a hypomorphic loss-of-function mutation that causes growth and neurodevelopmental defects, as well as cardiac conduction abnormalities in the mouse (see ANIMAL MODEL). (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Heterozygous loss-of-function DHX9 variants are associated with neurodevelopmental disorders: Human genetic and experimental evidences.	Yamada M	European journal of medical genetics	2023	PMID: 37369308

Text-mined citations for this variant ...

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001357.5(DHX9):c.1240G>A (p.Gly414Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...