Submissions for variant NM_172107.4(KCNQ2):c.2555C>T (p.Pro852Leu)

gnomAD frequency: 0.00001  dbSNP: rs745508762

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000762354	SCV000241540	uncertain significance	not provided	2018-10-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNQ2 gene. The P852L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P852L variant is not observed in large population cohorts (Lek et al., 2016). The P852L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Center for Human Genetics Tuebingen	RCV000762354	SCV000892662	uncertain significance	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302913	SCV001492140	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-07-09	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 852 of the KCNQ2 protein (p.Pro852Leu). 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. This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (PMID: 31164858). ClinVar contains an entry for this variant (Variation ID: 205936). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002485271	SCV002786760	uncertain significance	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7	2021-10-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020273	SCV004892948	likely benign	Inborn genetic diseases	2024-03-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.