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

dbSNP: rs796052641

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187889	SCV000241491	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 28191890, 28867141, 28135719, 25533962, 33754465, 31785789, 27602407, 35104249)
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV001089685	SCV001197999	likely pathogenic	Epicanthus; Autistic behavior; Seizure; Abnormal facial shape; Intellectual disability, moderate		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056663	SCV001221116	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-11-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. 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 KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 205892). This missense change has been observed in individual(s) with seizures and developmental delay (PMID: 25533962, 28867141; Invitae). 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 335 of the KCNQ2 protein (p.Pro335Leu).
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
Revvity Omics, Revvity	RCV000187889	SCV002023230	pathogenic	not provided	2020-09-14	criteria provided, single submitter	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315320	SCV004015027	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only