Submissions for variant NM_001356.5(DDX3X):c.874C>T (p.Arg292Ter)

dbSNP: rs1555953488

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519583	SCV000620988	pathogenic	not provided	2022-05-09	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: 30349862, 32135084, 33084842, 31785789, 33504798)
Ambry Genetics	RCV002314917	SCV000849278	pathogenic	Inborn genetic diseases	2017-03-31	criteria provided, single submitter	clinical testing	The p.R292* pathogenic mutation (also known as c.874C>T), located in coding exon 10 of the DDX3X gene, results from a C to T substitution at nucleotide position 874. This changes the amino acid from an arginine to a stop codon within coding exon 10. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000519583	SCV000939481	pathogenic	not provided	2018-09-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DDX3X are known to be pathogenic (PMID: 26235985). This variant has not been reported in the literature in individuals with DDX3X-related disease. ClinVar contains an entry for this variant (Variation ID: 452201). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg292*) in the DDX3X gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174975	SCV001338460	likely pathogenic	Intellectual disability, X-linked 102	2020-04-10	criteria provided, single submitter	clinical testing	Variant summary: DDX3X c.874C>T (p.Arg292X) 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 178756 control chromosomes (gnomAD). c.874C>T has been reported in the literature in a female individual affected with X-linked Intellectual Disability (Wang_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000519583	SCV001446491	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001174975	SCV001980687	pathogenic	Intellectual disability, X-linked 102	2020-07-14	criteria provided, single submitter	clinical testing	A heterozygous c.874C>T (p.Arg292Ter) variant in DDX3X was detected in this individual. This nonsense variant found in exon 10 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a de novo change in a female with developmental delay and/or intellectual disability (PMID: 30349862). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.874C>T (p.Arg292Ter) variant is classified as Pathogenic.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156102	SCV003845293	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000519583	SCV004010930	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	DDX3X: PVS1, PM2, PS4:Supporting
PreventionGenetics, part of Exact Sciences	RCV004527633	SCV004106952	pathogenic	DDX3X-related disorder	2023-07-05	criteria provided, single submitter	clinical testing	The DDX3X c.874C>T variant is predicted to result in premature protein termination (p.Arg292*). This variant has been reported as a de novo finding in individuals with Snijders Blok type X-linked syndromic intellectual developmental disorder (Wang et al. 2018. PubMed ID: 30349862; Lennox et al. 2020. PubMed ID: 32135084; Martin et al. 2021. PubMed ID: 33504798). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in DDX3X are expected to be pathogenic. This variant is interpreted as pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV001174975	SCV004177235	pathogenic	Intellectual disability, X-linked 102		criteria provided, single submitter	not provided
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001174975	SCV001428217	pathogenic	Intellectual disability, X-linked 102	2019-01-01	no assertion criteria provided	clinical testing
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	RCV001174975	SCV003840180	pathogenic	Intellectual disability, X-linked 102		no assertion criteria provided	clinical testing