ClinVar Miner

Submissions for variant NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del) (rs797044966)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001089683 SCV001245167 likely pathogenic Nonsyndromic hearing loss and deafness 2019-11-26 reviewed by expert panel curation The c.806_808delCCT (p.Ser269del) variant in KCNQ4 has been observed in at least 4 probands with hearing loss (PS4_Supporting; PMID: 23399560, 23443030, LMM unpublished data SCV000967428.1). This variant segregated with hearing loss in 12 additional individuals from 1 family (PP1_Strong; PMID: 23443030). The p.Ser269del variant was absent from large population studies (PM2; https://gnomad.broadinstitute.org). 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). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: PP1_Strong, PM2, PM4, PS4_Supporting.
GeneDx RCV000484405 SCV000568660 likely pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing The c.806_808delCCT variant in the KCNQ4 gene has been reported in at least two families with autosomal dominant hearing loss (Abdelfatah et al., 2013; Watabe et al., 2013). The c.806_808delCCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.806_808delCCT variant is an in-frame deletion that results in the loss of a single Serine residue, denoted p.Ser269del within the extracellular topological domain (Uniprot). The residue removed by this deletion occurs at a position where amino acids with similar properties to Serine are tolerated across species. Based on currently available evidence, we interpret c.806_808delCCT to be likely pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare 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.
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

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