ClinVar Miner

Submissions for variant NM_004700.4(KCNQ4):c.825G>C (p.Trp275Cys) (rs956666801)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000710319 SCV000840505 likely pathogenic Nonsyndromic hearing loss and deafness 2018-09-10 reviewed by expert panel curation The c.825G>C (p.Trp275Cys) variant was found in one patient with hearing loss (PS4 not met; Partners LMM ClinVar SCV000712456.1). The p.Trp275Cys variant in the KCNQ4 gene was absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org) (PM2). A different pathogenic missense variant (p.Trp275Arg) and a likely pathogenic missense variant (p.Trp275Ser) have 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 6242, PMID: 25116015, 20301388; ClinVar Variation ID 372951). 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). Computational prediction tools and conservation analysis suggest that the p.Trp275Cys variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant non-syndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: (PM2, PM5, PM1, PP3).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000599794 SCV000712456 uncertain significance not specified 2016-08-31 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Trp275Cys variant in KCNQ4 has not been previously reported in individuals with hearing l oss and was absent from large population studies. The tryptophan (Trp) at positi on 275 is highly conserved in mammals and evolutionarily distant species, and co mputational prediction tools suggest the p.Trp275Cys may impact the protein. In addition, a different missense variant at the same amino acid position (p.Trp275 Arg) has been previously reported in an individual with hearing loss and segrega ted in 11 affected relatives (Wang 2014). These data suggest that a change at th is position may not be tolerated, however additional data is needed to assume pa thogenicity for this missense variant. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Trp275Cys variant is uncertain.

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