VCV000503738.41 - ClinVar

NM_001356.5(DDX3X):c.1675CTT[1] (p.Leu560del)

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.

(8)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001356.5(DDX3X):c.1675CTT[1] (p.Leu560del)

Variation ID: 503738 Accession: VCV000503738.41

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: Xp11.4 X: 41346917-41346919 (GRCh38) [ NCBI UCSC ] X: 41206170-41206172 (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	Apr 2, 2018	Dec 22, 2024	Aug 9, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001356.5:c.1675CTT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001347.3:p.Leu560del	inframe deletion
NM_001356.5:c.1678_1680del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001193416.1:c.1678_1680delCTT
NM_001193416.3:c.1675CTT[1]	NP_001180345.1:p.Leu560del	inframe deletion
NM_001193417.3:c.1627CTT[1]	NP_001180346.1:p.Leu544del	inframe deletion
NM_001356.4:c.1678_1680del
NM_001363819.1:c.1117CTT[1]	NP_001350748.1:p.Leu374del	inframe deletion
NR_126093.1:n.2620CTT[1]		non-coding transcript variant
NC_000023.11:g.41346918CTT[1]
NC_000023.10:g.41206171CTT[1]
NG_012830.2:g.18521CTT[1]

... more HGVS ... less HGVS

Protein change

L560del, L544del, L374del

Other names

Canonical SPDI

NC_000023.11:41346916:TCTTCTT:TCTT

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: CA658799715 dbSNP: rs1555954380 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.
DDX3X		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	784	942

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.
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 15, 2022	RCV000599287.31
Intellectual disability, X-linked 102	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 9, 2022	RCV001255961.9
Intellectual disability	Pathogenic (1)	criteria provided, single submitter	Sep 10, 2020	RCV001260756.4

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.
Pathogenic (Sep 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: de novo	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001437848.1 First in ClinVar: Oct 10, 2020 Last updated: Oct 10, 2020	Zygosity: Single Heterozygote Method: targeted next-gen sequencing
Likely pathogenic (May 04, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked 102 Affected status: yes Allele origin: de novo	Baylor Genetics Accession: SCV001529640.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Publications: PubMed (1) PubMed: 26235985 Comment: This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in one … (more) This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as de novo in one patient with intellectual disability [PMID 26235985] (less)
Likely pathogenic (Oct 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064508.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely pathogenic (Aug 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked 102 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581631.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS2, PS4_SUP, PM2_SUP, PP2, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jul 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000710020.5 First in ClinVar: Apr 02, 2018 Last updated: Mar 04, 2023	Comment: Not observed in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and … (more) Not observed in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26235985, 31278258) (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, X-linked 102 Affected status: yes Allele origin: germline	Juno Genomics, Hangzhou Juno Genomics, Inc Accession: SCV005417143.1 First in ClinVar: Nov 30, 2024 Last updated: Nov 30, 2024	Comment: PM2_Supporting+PM4+PS4_Supporting+PS2_Moderate
Pathogenic (Jul 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250517.27 First in ClinVar: May 09, 2020 Last updated: Dec 22, 2024	Number of individuals with the variant: 2
Likely pathogenic (Sep 16, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability, X-linked 102 (X-linked inheritance) Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Stanford Medicine Accession: SCV001427075.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Comment: The p.Leu560del variant in the DDX3X gene has been previously reported de novo in 3 individuals with intellectual disability and other features including global developmental … (more) The p.Leu560del variant in the DDX3X gene has been previously reported de novo in 3 individuals with intellectual disability and other features including global developmental delay, vision issues, hypotonia, hyperlaxity, abnormal brain imaging, and microcephaly (GeneDx pers. comm., Sep 10, 2019; Snijders Blok et al., 2015). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Leu560del variant results in an in-frame deletion of 1 amino acid in the helicase C-terminal domain of DDX3X. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu560del variant as likely pathogenic for intellectual disability 102 in an X-linked dominant manner based on the information above. [ACMG evidence codes used: PS2; PM2; PP3] (less)

Comment:

Not observed in large population cohorts (gnomAD); In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26235985, 31278258)

Comment:

The p.Leu560del variant in the DDX3X gene has been previously reported de novo in 3 individuals with intellectual disability and other features including global developmental delay, vision issues, hypotonia, hyperlaxity, abnormal brain imaging, and microcephaly (GeneDx pers. comm., Sep 10, 2019; Snijders Blok et al., 2015). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Leu560del variant results in an in-frame deletion of 1 amino acid in the helicase C-terminal domain of DDX3X. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Leu560del variant as likely pathogenic for intellectual disability 102 in an X-linked dominant manner based on the information above. [ACMG evidence codes used: PS2; PM2; PP3]

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
Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.	Snijders Blok L	American journal of human genetics	2015	PMID: 26235985

Text-mined citations for rs1555954380 ...

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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_001356.5(DDX3X):c.1675CTT[1] (p.Leu560del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555954380 ...