Submissions for variant NM_003718.5(CDK13):c.2524A>G (p.Asn842Asp)

dbSNP: rs1554333853

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000625958	SCV000746556	likely pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2016-12-08	criteria provided, single submitter	clinical testing	This variant has been reported in PMID:28807008 (individual 1001).
Department of Medical Genetics, Oslo University Hospital	RCV000625958	SCV001437574	likely pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2016-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383184	SCV001582256	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with aspartic acid at codon 842 of the CDK13 protein (p.Asn842Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with CDK13-related disease (PMID: 28807008, 29021403). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 522794). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Asn842 amino acid residue in CDK13. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27479907, 28554332, 28807008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Daryl Scott Lab, Baylor College of Medicine	RCV000625958	SCV002072584	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2022-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001383184	SCV005370543	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28807008, 29021403, 29222009, 27479907)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000625958	SCV005878272	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2024-07-23	criteria provided, single submitter	clinical testing	The CDK13 c.2524A>G; p.Asn842Asp variant (rs1554333853, ClinVar Variation ID: 522794) is reported in the literature in at least two individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (Bostwick 2017, Hamilton 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. The asparagine at codon 842 is located in the active site of the protein kinase domain (Bostwick 2017), which is predicted to abolish kinase activity. In one study, more than half (15/29) of the CDK13 variants identified altered the 842 codon, supporting the importance of this codon in proper protein function (Bostwick 2017). Furthermore, a different variant at this codon (p.Asn842Ser) is classified as pathogenic by several laboratories in ClinVar (Variation ID: 235887). Computational analyses predict that the p.Asn842Asp variant is deleterious (REVEL: 0.88). Based on available information, this variant is considered to be pathogenic. References: Bostwick BL et al. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med. 2017;9(1):73. PMID: 28807008. Hamilton MJ et al. Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability. J Med Genet. 2018;55(1):28-38. PMID: 29021403.
OMIM	RCV000625958	SCV000680088	pathogenic	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder	2024-02-15	no assertion criteria provided	literature only
GeneReviews	RCV000625958	SCV001370886	not provided	Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder		no assertion provided	literature only