Submissions for variant NM_001356.5(DDX3X):c.1807C>T (p.Arg603Ter)

dbSNP: rs886041705

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000328364	SCV000330437	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32135084, 33258288, 36114283, 30349862)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000767345	SCV000897915	pathogenic	Intellectual disability, X-linked 102	2018-10-04	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000328364	SCV001215806	pathogenic	not provided	2023-01-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280514). This premature translational stop signal has been observed in individual(s) with clinical features of X-linked intellectual disability (PMID: 30349862). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg602*) in the DDX3X gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DDX3X are known to be pathogenic (PMID: 26235985).
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260598	SCV001437690	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000767345	SCV003922293	pathogenic	Intellectual disability, X-linked 102	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Arg603Ter variant in DDX3X was identified by our study in one individual with developmental delay, hypotonia, growth retardation, dysmorphic facial features, recurrent otitis media, feeding difficulties, and structural brain anomalies. The p.Arg603Ter variant in DDX3X has been previously reported in 4 unrelated individuals with DDX3X-related neurodevelopmental disorder (PMID: 36114283, PMID: 33258288, PMID: 32135084, PMID: 30349862). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 3 individuals with confirmed paternity and maternity (PMID: 36114283, PMID: 32135084, PMID: 30349862). This variant is assumed de novo in one individual, but paternity and maternity have not been confirmed (PMID: 33258288). This variant has also been reported in ClinVar (Variation ID: 280514) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 603, which is predicted to lead to a truncated or absent protein. Loss of function of the DDX3X gene is strongly associated to X-linked DDX3X-related neurodevelopmental disorder. In summary, this variant meets criteria to be classified as pathogenic for X-linked DDX3X-related neurodevelopmental disorder. ACMG/AMP Criteria applied: PVS1_Strong, PS2, PS4_Moderate, PM2_Supporting, PM6_Supporting (Richards 2015).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000328364	SCV001806958	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000328364	SCV001957468	likely pathogenic	not provided		no assertion criteria provided	clinical testing