ClinVar Genomic variation as it relates to human health

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in at least 5 probands with autosomal dominant hearing loss (PS4_Supporting; PMID: 23399560, 23443030, 34316018, LMM unpublished data SCV000967428.1).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).

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.

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)

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.