ClinVar Miner

Submissions for variant NM_004700.4(KCNQ4):c.682G>T (p.Gly228Cys)

gnomAD frequency: 0.00003  dbSNP: rs367890569
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000603791 SCV000711085 uncertain significance not specified 2017-02-16 criteria provided, single submitter clinical testing The p.Gly228Cys variant in KCNQ4 has not been previously reported in individuals with hearing loss, but has been identified in 1/51990 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3 67890569). Although this variant has been seen in the general population, its fr equency is not high enough to rule out a pathogenic role. Computational predicti on tools and conservation analysis suggest that the p.Gly228Cys variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the p.Gly228Cys variant is uncertain.
Fulgent Genetics, Fulgent Genetics RCV000763909 SCV000894850 uncertain significance Autosomal dominant nonsyndromic hearing loss 2A 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002532721 SCV003505863 uncertain significance not provided 2023-04-15 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 228 of the KCNQ4 protein (p.Gly228Cys). This variant is present in population databases (rs367890569, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with KCNQ4-related conditions. ClinVar contains an entry for this variant (Variation ID: 504603). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab RCV000763909 SCV004173164 uncertain significance Autosomal dominant nonsyndromic hearing loss 2A 2023-04-11 criteria provided, single submitter clinical testing

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