ClinVar Miner

Submissions for variant NM_004700.4(KCNQ4):c.853G>A (p.Gly285Ser) (rs28937588)

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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 RCV000211722 SCV000840524 pathogenic Nonsyndromic hearing loss and deafness 2018-09-11 reviewed by expert panel curation The p.Gly285Ser variant in the KCNQ4 gene was absent from the Genome Aggregation Database ( (PM2). The p.Gly285Ser variant has been reported to segregate with hearing loss in at least 16 family members (PP1_S; PMIDs: 10025409, 25116015). The variant meets PM2 and has been observed in at least 2 affected probands (PS4_P, PMID: 10025409, Partners LMM internal data SCV000198442.4). A different pathogenic missense variant (p.Gly285Cys) has 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 6244, PMID: 10369879). 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; A functional study demonstrates that this variant may impact protein function (PS3_P; PMID: 10025409, 18786918). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2, PP1_S, PS4_P, PM5, PM1, PS3_P.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844633 SCV000198442 pathogenic Rare genetic deafness 2018-10-23 criteria provided, single submitter clinical testing The p.Gly285Ser variant in KCNQ4 has been reported in at least three individuals with hearing loss, and segregated with disease in over 15 affected relatives fr om two families (LMM unpublished data, Kubisch 1999, Wang 2014). It was absent f rom large population studies. In vitro functional studies support an impact on p rotein function and suggest that the variant may act in a dominant-negative mann er (Kubisch 1999, Bal 2008). Furthermore, the p.Gly285Ser variant falls within t he highly conserved pore-forming region of KCNQ4 (Oza 2018). Supporting the into lerance of this position to variation, a different amino acid change at the same position (p.Gly285Cys) has been reported in one family with hearing loss (Couck e 1999). Finally, this variant was classified as Pathogenic on 9/11/2018 by the ClinGen-approved Hearing Loss Expert Panel (Variation ID 6241). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant no nsyndromic hearing loss. ACMG/AMP criteria applied: PP1_Strong, PM1, PM2, PP3, P S3_Supporting, PS4_Supporting.
OMIM RCV000006619 SCV000026802 pathogenic Autosomal dominant nonsyndromic hearing loss 2A 2011-01-14 no assertion criteria provided literature only
GeneReviews RCV000006619 SCV000041116 pathogenic Autosomal dominant nonsyndromic hearing loss 2A 2015-08-20 no assertion criteria provided literature only

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