ClinVar Miner

Submissions for variant NM_172107.4(KCNQ2):c.1004C>T (p.Pro335Leu) (rs796052641)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187889 SCV000241491 pathogenic not provided 2018-08-16 criteria provided, single submitter clinical testing The P335L variant in the KCNQ2 gene has been reported previously in association with intellectual disability and developmental disorders, as a de novo variant in two unrelated individuals (Lelieveld et al., 2017). The P335L variant is not observed in large population cohorts (Lek et al., 2016). The P335L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This substitution is predicted to be within the C-terminal cytoplasmic domain (Millichap et al., 2016). We interpret P335L as a pathogenic variant.
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement,Assistance Publique Hopitaux de Paris RCV001089685 SCV001197999 likely pathogenic Epicanthus; Autistic behavior; Seizures; Abnormal facial shape; Intellectual disability, moderate criteria provided, single submitter clinical testing
Invitae RCV001056663 SCV001221116 pathogenic Early infantile epileptic encephalopathy 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 335 of the KCNQ2 protein (p.Pro335Leu). 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 been observed de novo in individuals affected with seizures and developmental delay (PMID: 25533962, 28867141, Invitae). ClinVar contains an entry for this variant (Variation ID: 205892). 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro335 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000187889 SCV001430901 pathogenic not provided 2020-07-22 criteria provided, single submitter clinical testing PS2_VeryStrong, PM5_Supporting, PP2, PP3, PM1, PM2, PS4_Moderate

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.