Submissions for variant NM_003718.5(CDK13):c.2525A>G (p.Asn842Ser)

dbSNP: rs878853160

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000417211	SCV000281758	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2016-05-12	criteria provided, single submitter	research
GeneDx	RCV000498452	SCV000589447	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28554332, 28867141, 29393965, 31883531, 27479907, 28807008, 29021403, 29222009, 28135719, 24999027, 19344873, 25560765, 28991257, 31238879, 31036916, 29738522, 32277047, 32368696, 32901917, 31785789)
Ambry Genetics	RCV000622786	SCV000742245	pathogenic	Inborn genetic diseases	2017-03-15	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000498452	SCV000920567	pathogenic	not provided	2018-09-14	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000850464	SCV000992662	likely pathogenic	Marfanoid habitus and intellectual disability		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000498452	SCV001250331	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000417211	SCV001439317	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2020-07-22	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526523	SCV001736945	pathogenic	Global developmental delay		criteria provided, single submitter	clinical testing
3billion	RCV000417211	SCV002012180	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in a similarly affected individual (ClinVar ID: VCV000235887.20, PMID: 27479907 and 29021403, PS1, PS2 and PS4_M). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn842Asp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000522794.5, PMID: 28807008, 29021403, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.861, 3Cnet: 0.997, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000417211	SCV002556994	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2021-05-12	criteria provided, single submitter	clinical testing	The CDK13 c.2525A>G variant is classified as PATHOGENIC (PS4, PS2, PP3) The CDK13 c.2525A>G variant is a single nucleotide change in exon 6 of the CDK13 gene, which is predicted to change the amino acid asparagine at position 842 in the protein to serine. This recurrent variant has been identified in multiple individuals with global developmental delay or intellectual disability and dysmorphic features, with or without congenital heart defects, hypotonia or hearing loss (PMID:27479907, PMID:29021403, PMID:29222009) (PS4). A number of these cases have been shown to be de novo (PMID:28807008) (PS2). This variant is in dbSNP (rs878853160) but is absent from population databases (PM2). This variant has been reported in ClinVar as Pathogenic by multiple other diagnostic laboratories (Variation ID:235887), and has been reported as damaging for congenital heart disease, developmental delay and intellectual disability in HGMD (CM1610451). Computational predictions support a deleterious effect on the gene or gene product (PP3).
MGZ Medical Genetics Center	RCV000417211	SCV002578968	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-04-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000417211	SCV002769358	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, haploinsufficiency, dominant negative and gain of function have been suggested in the literature (PMIDs: 30904094, 29393965, 28807008) (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in the protein kinase domain (PDB), where disease-associated missense variants are clustered (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been reported in many patients and shown to be de novo in multiple patients (ClinVar, Deciphering Developmental Disorders (DDD) Study). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000417211	SCV002815704	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2021-09-22	criteria provided, single submitter	clinical testing
Invitae	RCV000498452	SCV003439941	pathogenic	not provided	2022-10-18	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CDK13 protein function. ClinVar contains an entry for this variant (Variation ID: 235887). This missense change has been observed in individual(s) with CDK13-related conditions (PMID: 28807008). In at least one individual the variant was observed to be de novo. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 842 of the CDK13 protein (p.Asn842Ser).
Baylor Genetics	RCV000417211	SCV003835390	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-08-12	criteria provided, single submitter	clinical testing
OMIM	RCV000417211	SCV000503042	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2024-02-15	no assertion criteria provided	literature only
GeneReviews	RCV000417211	SCV001370887	not provided	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder		no assertion provided	literature only
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000417211	SCV001442986	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2020-06-10	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000417211	SCV001450704	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2020-09-03	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000498452	SCV001741783	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000498452	SCV001806804	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000498452	SCV001956718	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000498452	SCV002036802	pathogenic	not provided		no assertion criteria provided	clinical testing