Submissions for variant NM_001347721.2(DYRK1A):c.638-9_638-5del

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000576181	SCV000677027	pathogenic	DYRK1A-related intellectual disability syndrome	2022-10-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 487250). This variant has been observed in individual(s) with DYRK1A-related disease (PMID: 25707398; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the DYRK1A gene. It does not directly change the encoded amino acid sequence of the DYRK1A protein. It affects a nucleotide within the consensus splice site.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000576181	SCV001423647	likely pathogenic	DYRK1A-related intellectual disability syndrome	2019-01-18	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PM2, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260680	SCV001437772	likely pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268095	SCV001446747	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268095	SCV002765792	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25707398, 28135719, 32371413, 28252636, 31526516, 33562844, 34345024)
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156105	SCV003845251	likely pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000576181	SCV003922009	pathogenic	DYRK1A-related intellectual disability syndrome	2021-05-07	criteria provided, single submitter	clinical testing	0102 - Loss of function is a known mechanism of disease in this gene and is associated with DYRK1A-related intellectual disability syndrome, MONDO: 0013578. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times in the ClinVar database, and twice in the literature as de novo in individuals with intellectual disability and other features (PMID: 25707398, 32371413). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000576181	SCV001432317	likely pathogenic	DYRK1A-related intellectual disability syndrome		no assertion criteria provided	clinical testing