NM_001356.5(DDX3X):c.1535_1536del (p.His512fs) AND Intellectual disability, X-linked 102

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 27, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001093539.18

Allele description [Variation Report for NM_001356.5(DDX3X):c.1535_1536del (p.His512fs)]

NM_001356.5(DDX3X):c.1535_1536del (p.His512fs)

Gene:

DDX3X:DEAD-box helicase 3 X-linked [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

Xp11.4

Genomic location:

Preferred name:

NM_001356.5(DDX3X):c.1535_1536del (p.His512fs)

HGVS:

NC_000023.11:g.41346542_41346543del
NG_012830.2:g.18145_18146del
NM_001193416.3:c.1535_1536del
NM_001193417.3:c.1487_1488del
NM_001356.5:c.1535_1536delMANE SELECT
NM_001363819.1:c.977_978del
NP_001180345.1:p.His512fs
NP_001180346.1:p.His496fs
NP_001347.3:p.His512fs
NP_001350748.1:p.His326fs
NC_000023.10:g.41205795_41205796del
NC_000023.10:g.41205795_41205796delAT
NM_001193416.1:c.1535_1536del
NM_001193416.1:c.1535_1536delAT
NM_001356.3:c.1535_1536delAT
NM_001356.4:c.1535_1536del
NM_001356.4:c.1535_1536delAT
NR_126093.1:n.2480_2481del
p.H512Rfs*5

Protein change:

H326fs

Links:

OMIM: 300160.0013; dbSNP: rs796052230

NCBI 1000 Genomes Browser:

rs796052230

Molecular consequence:

NM_001193416.3:c.1535_1536del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001193417.3:c.1487_1488del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001356.5:c.1535_1536del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001363819.1:c.977_978del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_126093.1:n.2480_2481del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Intellectual disability, X-linked 102 (MRXSSB)
Synonyms:: INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNIJDERS BLOK TYPE
Identifiers:: MONDO: MONDO:0010497; MedGen: C5393299; Orphanet: 457260; OMIM: 300958

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001250588	OMIM	no assertion criteria provided	Pathogenic (Jul 15, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001423698	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 23, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002098133	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002571991	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 12, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31618753, 32371413, 30817323, 26235985 Citation Link,
SCV004014004	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 27, 2022)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

Ziats MN, Ahmad A, Bernat JA, Fisher R, Glassford M, Hannibal MC, Jacher JE, Weiser N, Keegan CE, Lee KN, Marzulla TB, O'Connor BC, Quinonez SC, Seemann L, Turner L, Bielas S, Harris NL, Ogle JD, Innis JW, Martin DM.

Pediatr Res. 2020 Mar;87(4):735-739. doi: 10.1038/s41390-019-0611-5. Epub 2019 Oct 16.

PubMed [citation]

PMID:: 31618753
PMCID:: PMC7082194

Disease-associated mosaic variation in clinical exome sequencing: a two-year pediatric tertiary care experience.

Miller CR, Lee K, Pfau RB, Reshmi SC, Corsmeier DJ, Hashimoto S, Dave-Wala A, Jayaraman V, Koboldt D, Matthews T, Mouhlas D, Stein M, McKinney A, Grossman T, Kelly BJ, White P, Magrini V, Wilson RK, Mardis ER, Cottrell CE.

Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3). doi:pii: a005231. 10.1101/mcs.a005231. Print 2020 Jun.

PubMed [citation]

PMID:: 32371413
PMCID:: PMC7304353

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV001250588.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

By exome sequencing in a 10-year-old girl with Snijders Blok-type X-linked syndromic intellectual developmental disorder (MRXSSB; 300958), Chanes et al. (2019) identified a de novo heterozygous 2-bp deletion (c.1535_1536del) in the DDX3X gene, resulting in a frameshift and a premature termination codon (His512ArgfsTer5). The patient, who was born prematurely at 25 weeks' gestation, had impaired intellectual development, behavioral problems, and minor dysmorphic features.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital, SCV001423698.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

[ACMG/AMP: PVS1, PM1, PM2, PM6, PS4_Moderate] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is de novo in origin as it was not detected in the submitted parental specimens (identity NOT confirmed) [PM6], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV002098133.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Recurrent variant, observed de novo in 3 female probands [Snijders Blok et al 2015]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002571991.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: DDX3X c.1535_1536delAT (p.His512ArgfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 181440 control chromosomes (gnomAD). c.1535_1536delAT has been reported in the literature in several heterozygous female individuals affected with X-Linked Intellectual Disability 102, including at least three cases where it was confirmed to be de novo (Snijders Blok_2015, Chanes_2019, Ziats_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV004014004.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PVS1, PM2, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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