Submissions for variant NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)

dbSNP: rs797044966

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089683	SCV001245167	pathogenic	Nonsyndromic genetic hearing loss	2023-06-27	reviewed by expert panel	curation	The c.803_805CCT[1] (aka c.806_808del) variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 1 amino acid (p.Ser269del). It is absent from gnomAD v2.1.1 (PM2_Supporting). The variant has been reported in at least 5 probands with autosomal dominant hearing loss (PS4_Supporting; PMID: 23399560, 23443030, 34316018, LMM unpublished data SCV000967428.1). The variant has been observed to segregate with hearing loss in 12 affected individuals from 1 family (PP1_Strong; PMID: 23443030). This variant causes a change in the length of the protein due to an in-frame deletion between the S5 membrane-spanning domain and the pore region, which is important for protein function (PM4, PMID: 23717403). Patch-clamp studies in HEK293T cells revealed significantly reduced whole-cell potassium currents, and KCNQ openers did not rescue KCNQ4 mutant channels (PMID: 34316018, PS3_Moderate). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PM4, PS3_Moderate, PM2_Supporting, PS4_Supporting. (VCEP specifications version 2; 06.27.2023).
GeneDx	RCV000484405	SCV000568660	pathogenic	not provided	2023-07-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Lee et al., 2021); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20301388, 23399560, 33367117, 23443030, 34316018, 23717403, 30311386)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825943	SCV000967428	uncertain significance	not specified	2018-02-26	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser269del variant in KCNQ4 has been reported in 2 individuals with bilateral sloping hear ing loss and segregated with disease in 9 affected relatives from 1 family (Wata be 2013, Abdelfatah 2013). However, there was one individual with a similar hear ing loss pattern and two additional individuals with other forms of hearing loss that did not harbor the variant, as well as 7 family members with hearing loss on the other side of the family that did not harbor the variant (Abdelfatah 2013 ). The p.Ser269del variant was absent from large population studies and is repor ted in ClinVar (Variation ID# 204595). This variant is a deletion of 1 amino aci d at position 269 and is not predicted to alter the protein reading-frame. In su mmary, while there is some suspicion for a pathogenic role, the clinical signifi cance of the p.Ser269del variant is uncertain. ACMG/AMP Criteria applied: PP1_St rong, PM2, PS4_Supporting, BS4.
Invitae	RCV000484405	SCV004291790	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	This variant, c.806_808del, results in the deletion of 1 amino acid(s) of the KCNQ4 protein (p.Ser269del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant non-syndromic deafness (PMID: 23399560, 23443030). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208366). For these reasons, this variant has been classified as Pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000656422	SCV000778434	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2015-08-20	no assertion criteria provided	literature only