ClinVar Miner

Submissions for variant NM_172107.3(KCNQ2):c.1687G>A (p.Asp563Asn) (rs796052653)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720508 SCV000851385 pathogenic Seizures 2016-06-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000187917 SCV000510747 pathogenic not provided 2016-12-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763450 SCV000894226 pathogenic Benign familial neonatal seizures 1; Early infantile epileptic encephalopathy 7 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000187917 SCV000241519 pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing The D563N pathogenic variant in the KCNQ2 gene has been previously reported as a mosaic de novo variant in a patient with early-onset epilepsy and encephalopathy (Milh et al., 2015). This variant is not observed in large population cohorts (Lek et al., 2016). The D563N variant is asemi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is predicted to be within the C-terminal cytoplasmic domain of the KCNQ2 protein. Additionally, in-silico analyses, including proteinpredictors and evolutionary conservation, support a deleterious effect. Furthermore, a different missense variant in the same residue (D563E) as well as multiple missense variants in nearby residues (R560W, P561S, P561L) have been reported in the Human Gene Mutation Database in association with KCNQ2-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of D563N is consistent with the diagnosis of a KCNQ2-related disorder in this individual.
GeneReviews RCV000678190 SCV000484639 pathogenic Early infantile epileptic encephalopathy 7 2016-03-31 no assertion criteria provided literature only EE (epileptic encephalopathy)
Invitae RCV000810995 SCV000951238 pathogenic Early infantile epileptic encephalopathy 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 563 of the KCNQ2 protein (p.Asp563Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with benign familial neonatal seizures (PMID: 24107868) and early onset epileptic encephalopathy(PMID: 26007637). ClinVar contains an entry for this variant (Variation ID: 205917). 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"). The p.Asp563 amino acid residue in KCNQ2 has been determined to be clinically significant (PMID: 27334371, 23621294). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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