Submissions for variant NM_001323289.2(CDKL5):c.532C>T (p.Arg178Trp)

dbSNP: rs267608493

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000133373	SCV000190958	pathogenic	not provided	2019-12-26	criteria provided, single submitter	clinical testing	Not observed 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: 22430159, 23064044, 22670135, 24564546, 22998673, 26271793, 25657822, 30460546, 19793311, 19362436, 23242510, 22779007, 22678952, 29100083, 22872100, 26993267, 31031587, 32712949)
Invitae	RCV000544362	SCV000639479	pathogenic	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2023-03-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg178 amino acid residue in CDKL5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19793311, 22670135, 22678952, 26271793, 26482601). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 CDKL5 protein function. ClinVar contains an entry for this variant (Variation ID: 143823). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 19362436, 19793311, 22430159, 22678952, 22872100, 25657822, 26993267). 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 178 of the CDKL5 protein (p.Arg178Trp).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000169986	SCV000781090	pathogenic	Atypical Rett syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260657	SCV001437749	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345449	SCV002646833	pathogenic	Inborn genetic diseases	2019-06-06	criteria provided, single submitter	clinical testing	The p.R178W pathogenic mutation (also known as c.532C>T), located in coding exon 7 of the CDKL5 gene, results from a C to T substitution at nucleotide position 532. The arginine at codon 178 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple individuals with severe epileptic encephalopathy and/or Rett-syndrome like features (Artuso R et al. Brain Dev., 2010 Jan;32:17-24; Pini G et al. Neuropediatrics, 2012 Feb;43:37-43; Bahi-Buisson N et al. Am. J. Med. Genet. A, 2012 Jul;158A:1612-9), including in some cases as a confirmed de novo occurrence (Nemos C et al. Clin. Genet., 2009 Oct;76:357-71; Hamdan FF et al. Am. J. Hum. Genet., 2017 Nov;101:664-685). In addition, disease-causing alterations at the same codon have previously been reported, including p.R178P (Elia M et al. Neurology, 2008 Sep;71:997-9; Nemos C et al. Clin. Genet., 2009 Oct;76:357-71; Bahi-Buisson N et al. Am. J. Med. Genet. A, 2012 Jul;158A:1612-9), p.R178Q (Liang JS et al. Epilepsia, 2011 Oct;52:1835-42; Bahi-Buisson N et al. Am. J. Med. Genet. A, 2012 Jul;158A:1612-9), and p.R178L (Miao P et al. Clin. Genet., 2018 Dec;94:512-520). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000169915	SCV002757890	pathogenic	Developmental and epileptic encephalopathy, 2	2022-12-02	criteria provided, single submitter	clinical testing
RettBASE	RCV000169915	SCV000188387	likely pathogenic	Developmental and epileptic encephalopathy, 2	2014-05-15	no assertion criteria provided	curation	In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)
RettBASE	RCV000169986	SCV000222291	likely pathogenic	Atypical Rett syndrome	2014-05-15	no assertion criteria provided	curation	In silico prediction: SIFT = deleterious, MutationTaster = disease-causing, PolyPhen2 = probably damaging, AlignGVGD = benign (C0)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000133373	SCV000256045	pathogenic	not provided	2015-02-13	no assertion criteria provided	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV000169915	SCV004032228	pathogenic	Developmental and epileptic encephalopathy, 2		no assertion criteria provided	research