Submissions for variant NM_172107.4(KCNQ2):c.583T>C (p.Ser195Pro)

dbSNP: rs796052620

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187855	SCV000241455	pathogenic	not provided	2012-09-17	criteria provided, single submitter	clinical testing	p.Ser195Pro (TCT>CCT):c.583 T>C in exon 4 of the KCNQ2 gene (NM_172107.2)The Ser195Pro missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Ser195Pro in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a polar Serine is replaced by a non-polar Proline, and the gain of a bulky Proline residue may alter the secondary structure of the protein. Ser195Pro alters a highly conserved position in the linker region between the S3 and S4 transmembrane segments of the protein. Some in silico algorithms predict Ser195Pro may be damaging to protein structure/function, although one model suggests it is benign. Therefore, based on the currently available information, it is unclear whether Ser195Pro is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae	RCV000808224	SCV000948320	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2022-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ2 protein function. ClinVar contains an entry for this variant (Variation ID: 205866). This missense change has been observed in individual(s) with clinical features of KCNQ2-related conditions (PMID: 24107868; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 195 of the KCNQ2 protein (p.Ser195Pro).
GeneReviews	RCV000678127	SCV000484563	not provided	Developmental and epileptic encephalopathy, 7		no assertion provided	literature only	Infantile spasms