Submissions for variant NM_001323289.2(CDKL5):c.2555C>T (p.Pro852Leu) (rs587783156)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000144835	SCV000191074	uncertain significance	not provided	2017-01-23	criteria provided, single submitter	clinical testing	The Pro852Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Pro852Leu in approximately 6,400 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although Proline and Leucine are both uncharged, non-polar amino acids, the loss of a bulky Proline residue may alter the secondary structure of the protein. However, it alters a poorly conserved position in the C-terminal region of the protein, and missense mutations have not been reported at nearby amino acids. Several in silico algorithms predict Pro852Leu may be damaging to protein structure/function, although another model suggests it may be benign. Therefore, based on the currently available information, it is unclear whether Pro852Leu is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae	RCV001053868	SCV001218151	uncertain significance	Early infantile epileptic encephalopathy 2; Angelman syndrome-like	2019-04-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 852 of the CDKL5 protein (p.Pro852Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDKL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 156690). 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: "Benign"; Align-GVGD: "Class C15"). 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.

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