NM_001356.5(DDX3X):c.1582C>T (p.Arg528Cys) AND Intellectual disability, X-linked 102

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 25, 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:: RCV001824802.3

Allele description [Variation Report for NM_001356.5(DDX3X):c.1582C>T (p.Arg528Cys)]

NM_001356.5(DDX3X):c.1582C>T (p.Arg528Cys)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.4

Genomic location:

Preferred name:

NM_001356.5(DDX3X):c.1582C>T (p.Arg528Cys)

Other names:

NM_001356.5(DDX3X):c.1582C>T; p.Arg528Cys

HGVS:

NC_000023.11:g.41346589C>T
NG_012830.2:g.18192C>T
NM_001193416.3:c.1582C>T
NM_001193417.3:c.1534C>T
NM_001356.5:c.1582C>TMANE SELECT
NM_001363819.1:c.1024C>T
NP_001180345.1:p.Arg528Cys
NP_001180346.1:p.Arg512Cys
NP_001347.3:p.Arg528Cys
NP_001350748.1:p.Arg342Cys
NC_000023.10:g.41205842C>T
NC_000023.10:g.41205842C>T
NM_001193416.1:c.1582C>T
NM_001356.4:c.1582C>T
NR_126093.1:n.2527C>T

Protein change:

R342C

Links:

dbSNP: rs1064795323

NCBI 1000 Genomes Browser:

rs1064795323

Molecular consequence:

NM_001193416.3:c.1582C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001193417.3:c.1534C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001356.5:c.1582C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001363819.1:c.1024C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_126093.1:n.2527C>T - 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
SCV002074431	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 25, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32135084, 33692367 Citation Link,
SCV002568403	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 25, 2022)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002074431

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 25, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002568403

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 25, 2022)

germline

curation

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	germline	yes	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development.

Lennox AL, Hoye ML, Jiang R, Johnson-Kerner BL, Suit LA, Venkataramanan S, Sheehan CJ, Alsina FC, Fregeau B, Aldinger KA, Moey C, Lobach I, Afenjar A, Babovic-Vuksanovic D, Bézieau S, Blackburn PR, Bunt J, Burglen L, Campeau PM, Charles P, Chung BHY, Cogné B, et al.

Neuron. 2020 May 6;106(3):404-420.e8. doi: 10.1016/j.neuron.2020.01.042. Epub 2020 Mar 4.

PubMed [citation]

PMID:: 32135084
PMCID:: PMC7331285

easyCLIP analysis of RNA-protein interactions incorporating absolute quantification.

Porter DF, Miao W, Yang X, Goda GA, Ji AL, Donohue LKH, Aleman MM, Dominguez D, Khavari PA.

Nat Commun. 2021 Mar 10;12(1):1569. doi: 10.1038/s41467-021-21623-4.

PubMed [citation]

PMID:: 33692367
PMCID:: PMC7946914

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002074431.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: DDX3X c.1582C>T (p.Arg528Cys) results in a non-conservative amino acid change located in the Helicase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 180053 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1582C>T has been reported in the literature in one individual affected with X-Linked Intellectual Disability 102 at de novo status (Lennox_2020). At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant resulted in decreased RNA interaction (Porter_2021). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely 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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV002568403.1

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

Description

The heterozygous p.Arg528Cys variant in DDX3X was identified in 1 female individual with a neurodevelopmental disorder including delayed speech and language development, intellectual disability, seizure, and delayed ability to walk via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Trio exome analysis showed this variant to be de novo. The p.Arg528Cys variant in DDX3X was also found to be de novo in 2 individuals with neurodevelopmental disorder (PMID: 32135084, 33504798), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID#: 421724) and has been interpreted as pathogenic or likely pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp) and GeneDx. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in DDX3X in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for X-linked neurodevelopmental disorder. ACMG/AMP Criteria applied: PS2_moderate, PP2, PP3_moderate, PM2_supporting, PS4_supporting (Richards 2015).

#	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

Last Updated: Mar 30, 2024

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