ClinVar Genomic variation as it relates to human health

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000375737). The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.99). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28135719, 29021403, 29222009, 27479907, 28867141, 30904094, 33004838, 31785789)

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: 375737). This missense change has been observed in individual(s) with CDK13-related conditions (PMID: 27479907, 28135719, 29222009). 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 replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 717 of the CDK13 protein (p.Gly717Arg).

The c.2149G>A (p.G717R) alteration is located in exon 4 (coding exon 4) of the CDK13 gene. This alteration results from a G to A substitution at nucleotide position 2149, causing the glycine (G) at amino acid position 717 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with CDK13-related neurodevelopmental disorder including global developmental delays/intellectual disability and dysmorphic features. Structural brain abnormalities and congenital heart defects have been noted in some individuals (Sifrim, 2016; Marwaha, 2022; Deciphering Developmental Disorders, 2017; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. The p.G717 amino acid is located in the protein kinase domain of CDK13 (Kohoutek, 2012), in particular in a highly conserved GEGTYG G-loop motif. This highly conserved motif regulates cyclin dependent kinase function in the following way: (1) the p.G712, p.G714, and p.G717 amino acid residues form a structural motif to ensure primary function; (2) the p.T715 and p.Y716 amino acid residues function as inhibitory sites; and (3) the p.Y716 residue interacts with the substrate backbone (Bártová, 2005). The p.G717 amino acid is essential in forming this G-loop, which functions in all protein kinases in nucleotide alignment, phosphorylation site regulatory function, formation of substrate binding box, and specificity for phosphorylation (Bártová, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The heterozygous p.Gly717Arg variant in CDK13 was identified by our study in one individual with Duane retraction syndrome; atrial septal defect; hypotonia; speech, language, and motor delays; and dysmorphic facial features, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Trio exome analysis showed this variant to be de novo. We believe this is a phenotype expansion for CDK13-related disorders. The variant has been previously reported in at least 11 unrelated individuals with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (PMID: 35043535, PMID: 33004838, PMID: 27479907, PMID: 29222009, PMID: 29021403, PMID: 28135719, ClinVar Accession SCV001190260.1, SCV001738366.1, SCV000803694.1, SCV002521011.1). 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 10 individuals with confirmed paternity and maternity (PMID: 35043535, PMID: 33004838, PMID: 27479907, PMID: 29222009, PMID: 29021403, SCV000803694.1, SCV001738366.1, SCV001190260.1, PMID: 28135719). Multiple variants in the same region as the p.Gly717Arg variant have been reported in association with disease in the literature and in ClinVar, and the p.Gly717Arg variant is located in a region of CDK13 that is essential to its function as a protein kinase, suggesting that this variant is in a hot spot/functional domain and supports pathogenicity (PMID: 29021403; ClinVar ID: 375738, 977619, 449224). This variant has also been reported in ClinVar (Variation ID: 375737) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant congenital heart defects, dysmorphic facial features, and intellectual developmental disorder. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM1, PM2_Supporting, PP3 (Richards 2015).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (MIM#617360). Dominant negative has also been suggested as a mechanism of disease, although not proven with functional studies (PMIDs: 29393965, 30904094, 32762766). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (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) 0600 - Variant is located in the annotated protein kinase domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as de novo in over five individuals affected with CDK13-related conditions (DECIPHER). (SP) 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

CDK13: PS2, PM1, PM2, PS4:Moderate, PP2, PP3

Variant confirmed as disease-causing by referring clinical team