Submissions for variant NM_172107.4(KCNQ2):c.1229del (p.Pro410fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000408251	SCV000329803	pathogenic	not provided	2016-10-11	criteria provided, single submitter	clinical testing	The c.1229delC pathogenic variant in the KCNQ2 gene has been reported previously in association with neonatal convulsions (Volkers et al., 2009). Due to use of alternative nomenclature, this variant was reported as P410fs12X in this study (Volkers et al., 2009). Functional studies show that this variant impairs the function as well as trafficking of the KCNQ2 protein (Volkers et al., 2009). The deletion causes a frameshift starting with codon Proline 410, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Pro410ArgfsX30. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, it was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001004684	SCV001164141	pathogenic	Seizures, benign familial neonatal, 1	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003588607	SCV004297358	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-10	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 280043). This variant has not been reported in the literature in individuals affected with KCNQ2-related conditions. This sequence change creates a premature translational stop signal (p.Pro410Argfs*30) 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).

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