Submissions for variant NM_172107.4(KCNQ2):c.1741C>T (p.Arg581Ter)

gnomAD frequency: 0.00001  dbSNP: rs118192236

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187920	SCV000241522	pathogenic	not provided	2019-09-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14534157, 25525159, 25982755, 26993267, 31199083)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000636351	SCV000757790	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2024-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg581*) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157, 23692823, 27779742). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with benign familial neonatal seizures (PMID: 14534157, 25982755, 26993267). ClinVar contains an entry for this variant (Variation ID: 21768). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000678061	SCV001980686	pathogenic	Seizures, benign familial neonatal, 1	2020-07-11	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in families with benign familial neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000187920	SCV003826515	pathogenic	not provided	2022-01-07	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335050	SCV004046328	pathogenic	KCNQ2-related disorder		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 15 of 17 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change, predominantly inherited from an affected parent but also as a de novo change, in individuals with neonatal seizures (PMID: 14534157, 31199083, 26993267, 25982755, 19380078, 32863083, 34153113). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the maternal sample was negative for the c.1741C>T (p.Arg581Ter) variant. Based on the available evidence, the c.1741C>T (p.Arg581Ter) variant is classified as Pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004554609	SCV005043791	pathogenic	Seizure	2024-05-14	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000678061	SCV005398284	pathogenic	Seizures, benign familial neonatal, 1	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with developmental and epileptic encephalopathy 7 (DEE; MIM#613720) and benign neonatal seizures 1 (BFNS1; MIM#121200), respectively (PMID: 20437616). There is currently no phenotypic correlation in terms of variant types or location (PMID: 31418850). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance; however, this is only reported for individuals with BFNS1 (PMID: 25959266). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed in families with benign familial neonatal seizures (PMIDs: 25982755, 31199083). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneReviews	RCV000678061	SCV000041620	not provided	Seizures, benign familial neonatal, 1		no assertion provided	literature only	BFNE (benign familial neonatal epilepsy)
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000678061	SCV001752421	pathogenic	Seizures, benign familial neonatal, 1		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003335050	SCV004228791	not provided	KCNQ2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 01-31-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.