Submissions for variant NM_004519.4(KCNQ3):c.2611C>G (p.Pro871Ala)

dbSNP: rs200647826

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414374	SCV000490581	uncertain significance	not specified	2016-12-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNQ3 gene. The P871A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P871A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P871A 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 across species. However, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000660534	SCV000782637	uncertain significance	Seizures, benign familial neonatal, 2	2017-03-16	criteria provided, single submitter	clinical testing
Invitae	RCV001044531	SCV001208333	uncertain significance	Benign neonatal seizures	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 871 of the KCNQ3 protein (p.Pro871Ala). This variant is present in population databases (rs200647826, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal dominant KCNQ3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 372395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ3 protein function. 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.