Submissions for variant NM_172107.4(KCNQ2):c.2126dup (p.Val710fs)

dbSNP: rs1555850842

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479554	SCV000566280	pathogenic	not provided	2015-04-13	criteria provided, single submitter	clinical testing	The c.2126dupC duplication in the KCNQ2 gene causes a frameshift starting with codon Valine 710, changesthis amino acid to a Cysteine residue and creates a premature Stop codon at position 155 of the new readingframe, denoted p.Val710CysfsX155. Thisvariant is predicted to cause loss of normal protein functionthrough protein truncation, as the last 163 amino acids of the KCNQ2 protein are lost and replaced with 154incorrect amino acids. Although this duplication has not been previously reported to our knowledge, othertruncating variants in the KCNQ2 gene have been reported in association with KCNQ2-related disorders(Stenson et al., 2014). Therefore, we interpret this variant as pathogenic.
Invitae	RCV001389017	SCV001590221	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2021-05-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the KCNQ2 protein. Other variant(s) that disrupt this region (p.Lys829Serfs*35) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with clinical features of KCNQ2-related conditions (PMID: 29655203, 32581362). ClinVar contains an entry for this variant (Variation ID: 418894). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change results in a premature translational stop signal in the KCNQ2 gene (p.Val710Cysfs*155). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 163 amino acid(s) of the KCNQ2 protein.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335347	SCV004046094	pathogenic	KCNQ2-Related Disorders		criteria provided, single submitter	clinical testing	This frameshift variant in the last exon of KCNQ2 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through protein truncation. This variant has been previously reported as a heterozygous change in two patients with epilepsy and/or neurodevelopmental disorder (PMID: 29655203, 32581362). Additionally, other nonsense/frameshift variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 29655203, 31418850, 32712949). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.2126dup (p.Val710CysfsTer155) variant is classified as Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003633	SCV001162060	likely pathogenic	Epileptic encephalopathy		no assertion criteria provided	research