Submissions for variant NM_172107.4(KCNQ2):c.1732A>G (p.Met578Val)

dbSNP: rs1057516123

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480958	SCV000569469	pathogenic	not provided	2024-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the C-terminal cytoplasmic domain.; This variant is associated with the following publications: (PMID: 20437616, 31418850, 35104249, 25982755)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850942	SCV002293435	likely pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-07-09	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 578 of the KCNQ2 protein (p.Met578Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 25982755). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 369807). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 35104249). This variant disrupts the p.Met578 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24371303). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneReviews	RCV000678193	SCV000484642	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy)
Channelopathy-Associated Epilepsy Research Center	RCV003315343	SCV004015028	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only