Submissions for variant NM_001323289.2(CDKL5):c.59G>T (p.Gly20Val)

dbSNP: rs786204962

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001507056	SCV001712022	pathogenic	CDKL5 disorder	2021-03-26	reviewed by expert panel	curation	The p.Gly20Val variant in CDKL5 occurs in the de novo state (biological parentage confirmed) in this individual (PS2). Multiple pathogenic missense variants have been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 23064044, 20397747) (PM5_Strong). The p.Gly20Val variant in CDKL5 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Gly20Val variant in CDKL5 is classified as pathogenic for CDKL5-associated disorder based on the ACMG/AMP criteria (PS2, PM5_strong, PM2_supporting, PP3).
Genetic Services Laboratory, University of Chicago	RCV001819879	SCV002069325	likely pathogenic	not provided	2019-01-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CDKL5 gene demonstrated a sequence change, c.59G>T, in the apparent heterozygous state in an affected male individual, in exon 2 that results in an amino acid change, p.Gly20Val. This sequence change does not appear to have been previously described in patients with CDKL5-related disorders and has also not been described as a known benign sequence change in the CDKL5 gene. However, different pathogenic sequence changes affecting the same amino acid residue (p.Gly20Arg and p.Gly20Asp) have been described in patients with epileptic encephalopathy (White et al., 2010; Raymond et al., 2013). The p.Gly20Val change affects a highly conserved amino acid residue located in the ATP-binding domain of the CDKL5 protein where other missense pathogenic changes have been described. The presence of the c.59G>T (p.Gly20Val) variant in the apparent heterozygous state in this male patient is indicative of it having risen somatically and being in the mosaic state. This variant was seen to be present in approximately 27% of reads by next generation sequencing. Sanger sequencing confirmed the presence of this variant with the variant allele peak being a lot smaller than the normal allele peak on the sequence chromatogram, supporting the next generation sequencing finding. This sequence change is likely pathogenic; however functional studies have not been performed to prove this conclusively.
GenomeConnect, ClinGen	RCV001175282	SCV001338891	not provided	Angelman syndrome; Developmental and epileptic encephalopathy, 2		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 01-11-2019 by Lab or GTR ID 1238. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.