Submissions for variant NM_004700.4(KCNQ4):c.961G>A (p.Gly321Ser)

gnomAD frequency: 0.00001  dbSNP: rs28939710

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195307	SCV001365632	likely pathogenic	Rare genetic deafness	2020-10-14	criteria provided, single submitter	clinical testing	The p.Gly321Ser variant in KCNQ4 has been previously reported to segregate with autosomal dominant hearing loss in multiple individuals from a large Dutch family (Coucke 1999 PMID: 10369879, Van Camp 1997 PMID: 9126484). It has also been identified in 0.006% (1/15414) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is present in ClinVar (Variation ID 6243). Functional studies indicate that the variant results in a dominant negative effect (Leitner 2012 PMID: 21951272, Gao 2013 PMID: 23750663), and computational tools and conservation analyses also suggest an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PP1_Moderate, PM2, PP3, PS3_Supporting.
Invitae	RCV002512842	SCV003522655	likely pathogenic	not provided	2022-01-05	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 20966080, 23750663, 26515070). 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: 6243). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 10369879; Invitae). This variant is present in population databases (rs28939710, gnomAD 0.007%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the KCNQ4 protein (p.Gly321Ser).
GeneDx	RCV002512842	SCV003931052	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.(G321S) results in non-functional channels and significantly reduces KCNQ4 trafficking (Kim et al., 2011; Gao et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34316018, 28340560, 23399560, 25525159, 31541171, 21951272, 26036578, 9126484, 8035838, 27619418, 18797286, 23776385, 25116015, 23717403, 11556850, 30556268, 27704564, 17033161, 36140355, 12408061, 24616153, 11252765, 28802383, Zhang2021[Review], 26515070, 10369879, 34824372, 34732400, 20966080, 23750663)
Genome-Nilou Lab	RCV000006621	SCV004173286	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000006621	SCV000026804	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2019-11-22	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000006621	SCV000777820	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2015-08-20	no assertion criteria provided	literature only
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000006621	SCV000902326	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2019-02-26	no assertion criteria provided	case-control