Submissions for variant NM_172107.4(KCNQ2):c.1734_1735delinsAA (p.Met578_Leu579delinsIleMet)

dbSNP: rs796052665

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187944	SCV000241547	pathogenic	not provided	2014-07-30	criteria provided, single submitter	clinical testing	c.1734_1735delGCinsAA: p.Met578_Leu579delinsIleMet (M578_L579delinsIM) in exon 15 of the KCNQ2 gene (NM_172107.2). The normal sequence with the bases that are deleted in braces followed by the inserted bases in brackets is: ACAT{GC}[AA]TGTC.The c.1734_1735delGCinsAA mutation results in two missense substitutions on the same allele (in cis), M578I and L579M and are denoted p.Met578_Leu579delinsIleMet.The M578I 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. M578I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, M578I alters a highly conserved position in the subunit interaction domain of the protein, and other missense mutations in this region have been reported in association with KCNQ2-related disorders. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the M578I missense change has been seen previously at GeneDx. Therefore, we interpret M578I to be a disease-causing mutation. The L579M 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. L579M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, L579M alters a highly conserved position in the subunit interaction domain of the protein, and other missense mutations in this region have been reported in association with KCNQ2-related disorders. In silico analysis predicts this variant is probably damaging to the protein structure/function. The variant is found in EPILEPSY panel(s).
GeneReviews	RCV000678195	SCV000484644	pathogenic	Developmental and epileptic encephalopathy, 7	2016-03-31	no assertion criteria provided	literature only	EE (epileptic encephalopathy)