ClinVar Miner

Submissions for variant NM_153676.4(USH1C):c.1430G>A (p.Arg477Gln) (rs146333270)

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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, Partners HealthCare Personalized Medicine RCV000041254 SCV000064945 uncertain significance not specified 2018-04-24 criteria provided, single submitter clinical testing The p.Arg477Gln variant in USH1C has been previously reported by our laboratory in the heterozygous state in two individuals with hearing loss, one of whom har bored two pathogenic variants in another gene. This variant has been identified in 77/277120 of the total chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org/; dbSNP rs146333270). Although this variant h as been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis suggest that the p.Arg477Gln variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, the clini cal significance of the p.Arg477Gln variant is uncertain. ACMG/AMP Criteria appl ied: PM2_Supporting; PP3.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756869 SCV000884832 uncertain significance not provided 2017-10-03 criteria provided, single submitter clinical testing The p.Arg477Gln variant (rs146333270) has been reported as a ‘probably neutral variant’ in at least one individual with Usher syndrome; however, inheritance and specific clinical information were not reported (Le Quesne Stabej 2012). The p.Arg477Gln variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.028% (identified in 77 out of 277,120 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 47979). The arginine at codon 477 is moderately conserved considering 12 species (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the USH1C protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Arg477Gln variant cannot be determined with certainty.
Invitae RCV000756869 SCV001048125 likely benign not provided 2020-11-02 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375297 SCV001571871 uncertain significance Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PM2_Supporting, PP3_Supporting

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