Submissions for variant NM_172107.4(KCNQ2):c.844G>A (p.Asp282Asn)

dbSNP: rs796052636

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187881	SCV000241483	pathogenic	not provided	2015-06-16	criteria provided, single submitter	clinical testing	p.Asp282Asn (GAC>AAC): c.844 G>A in exon 6 of the KCNQ2 gene (NM_172107.2)The Asp282Asn missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as a negatively charged Aspartic acid residue is replaced by an uncharged Asparagine residue. Asp282Asn alters a highly conserved position in the pore-forming loop between the fifth and sixth transmembrane domains of the KCNQ2 protein, where other missense mutations have been reported in association with epilepsy. In addition, multiple in-silico algorithms predict Asp282Asn may be damaging to the structure/function of the protein. Therefore, based on the currently available information, Asp282Asn is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded. The variant is found in INFANT-EPI panel(s).
Invitae	RCV001377992	SCV001575460	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2020-01-29	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 27602407). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205884). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 282 of the KCNQ2 protein (p.Asp282Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. 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 C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp282 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28133863, 25533962). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.