Submissions for variant NM_004700.4(KCNQ4):c.853G>A (p.Gly285Ser)

dbSNP: rs28937588

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000211722	SCV000840524	pathogenic	Nonsyndromic genetic hearing loss	2018-09-11	reviewed by expert panel	curation	The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID: 10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has been previously identified at this codon of KCNQ4 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar Variation ID 6244, PMID: 10369879). Furthermore, the variant is in a location that has been defined by the ClinGen Hearing Loss Expert Panel to be a mutational hotspot or domain of KCNQ4 (PM1; PMID: 23717403; https://www.uniprot.org/uniprot/P56696). A functional study demonstrates that this variant may impact protein function (PS3_P; PMID: 10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844633	SCV000198442	pathogenic	Rare genetic deafness	2018-10-23	criteria provided, single submitter	clinical testing	The p.Gly285Ser variant in KCNQ4 has been reported in at least three individuals with hearing loss, and segregated with disease in over 15 affected relatives fr om two families (LMM unpublished data, Kubisch 1999, Wang 2014). It was absent f rom large population studies. In vitro functional studies support an impact on p rotein function and suggest that the variant may act in a dominant-negative mann er (Kubisch 1999, Bal 2008). Furthermore, the p.Gly285Ser variant falls within t he highly conserved pore-forming region of KCNQ4 (Oza 2018). Supporting the into lerance of this position to variation, a different amino acid change at the same position (p.Gly285Cys) has been reported in one family with hearing loss (Couck e 1999). Finally, this variant was classified as Pathogenic on 9/11/2018 by the ClinGen-approved Hearing Loss Expert Panel (Variation ID 6241). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant no nsyndromic hearing loss. ACMG/AMP criteria applied: PP1_Strong, PM1, PM2, PP3, P S3_Supporting, PS4_Supporting.
Invitae	RCV002512841	SCV003523272	pathogenic	not provided	2022-08-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly285 amino acid residue in KCNQ4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8035838, 10369879, 20832469, 20966080, 23717403). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 10025409, 20966080, 23750663). 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 KCNQ4 protein function. ClinVar contains an entry for this variant (Variation ID: 6241). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10025409, 25116015). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 285 of the KCNQ4 protein (p.Gly285Ser).
OMIM	RCV000006619	SCV000026802	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2011-01-14	no assertion criteria provided	literature only
GeneReviews	RCV000006619	SCV000041116	not provided	Autosomal dominant nonsyndromic hearing loss 2A		no assertion provided	literature only