Submissions for variant NM_001323289.2(CDKL5):c.1892T>C (p.Ile631Thr)

gnomAD frequency: 0.00012  dbSNP: rs144878564

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002281061	SCV002569932	benign	CDKL5 disorder	2022-08-25	reviewed by expert panel	curation	The allele frequency of the p.Ile631Thr variant in CDKL5 is 0.03% in African sub population in gnomAD, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). The p.Ile631Thr variant is observed in at least 2 unaffected individuals (internal database) (BS2). The p.Ile631Thr variant is observed in the CDKL5 gene where a second pathogenic variant in the same gene is present in the patient (PMID 19793311) (BP2). In summary, the p.Ile631Thr variant in CDKL5 is classified as benign based on the ACMG/AMP criteria (BA1, BS2, BP2).
Eurofins Ntd Llc (ga)	RCV000725189	SCV000334780	uncertain significance	not provided	2015-09-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000725189	SCV000729863	likely benign	not provided	2020-04-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19793311)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659290	SCV000781094	uncertain significance	Developmental and epileptic encephalopathy, 2	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700107	SCV000828848	uncertain significance	Developmental and epileptic encephalopathy, 2; Angelman syndrome-like	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 631 of the CDKL5 protein (p.Ile631Thr). This variant is present in population databases (rs144878564, gnomAD 0.02%). This missense change has been observed in individual(s) with seizures (PMID: 19793311). ClinVar contains an entry for this variant (Variation ID: 143786). 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 not expected to disrupt CDKL5 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002408638	SCV002723885	uncertain significance	Inborn genetic diseases	2017-08-02	criteria provided, single submitter	clinical testing	The p.I631T variant (also known as c.1892T>C), located in coding exon 11 of the CDKL5 gene, results from a T to C substitution at nucleotide position 1892. The isoleucine at codon 631 is replaced by threonine, an amino acid with similar properties. This alteration was detected as maternally inherited in an individual with early onset seizures (Nemos C et al. Clin. Genet., 2009 Oct;76:357-71). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Centre for Population Genomics, CPG	RCV002281061	SCV005335176	benign	CDKL5 disorder	2024-09-13	criteria provided, single submitter	curation	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as benign. At least the following criteria are met: The allele frequency of this variant in at least one population in gnomAD is higher than the 0.03% threshold defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders VCEP 3.0 (BA1).
RettBASE	RCV000133333	SCV000188342	likely benign	not specified	2014-05-09	no assertion criteria provided	curation	Identified in unaffect female with random X-inactivation pattern; in silico predictions: SIFT = tolerated, MutationTaster = polymorphism, PolyPhen2 = benign, AlignGVGD = benign (C0)