ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.3547_3548del (p.Ile1183fs)

dbSNP: rs397518013
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004618 SCV000927012 likely pathogenic Usher syndrome 2022-11-22 reviewed by expert panel curation The p.Ile1183fs variant in USH2A introduces a premature stop codon in biologically-relevant-exon 17/72 that is predicted to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9624053, 25211151, 20497194). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00088% (1/113352 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). One proband with autosomal recessive retinitis pigmentosa was identified to be carrying the p.Ile1183fs variant with no variant reported in trans (PMID: 35266249). This variant was re-reviewed on 11/22/2022 and because no additional evidence is available, professional judgment was used to retain this variant as likely pathogenic for autosomal recessive Usher Syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PVS1, PM2_P (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000824789 SCV000065525 pathogenic Rare genetic deafness 2011-03-31 criteria provided, single submitter clinical testing The Ile1183fs variant in USH2A has not been reported in the literature nor previ ously identified by our laboratory. The Ile1183fs variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1183 and leads to a premature stop codon 18 codons downstream. This alteration i s then predicted to lead to a truncated or absent protein. In summary, this vari ant meets our criteria to be classified as pathogenic.
Illumina Laboratory Services, Illumina RCV000301597 SCV000354129 uncertain significance USH2A-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The USH2A c.3547_3548delAT (p.Ile1183PhefsTer19) variant results in a frameshift and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00206 in the European American population of the Exome Sequencing Project. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000041829 SCV000487429 likely pathogenic Usher syndrome type 2A 2016-08-18 criteria provided, single submitter clinical testing
Counsyl RCV000410392 SCV000487430 likely pathogenic Retinitis pigmentosa 39 2016-08-18 criteria provided, single submitter clinical testing
Invitae RCV001388470 SCV001589469 pathogenic not provided 2023-10-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile1183Phefs*19) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397518013, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48503). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000410392 SCV004208289 pathogenic Retinitis pigmentosa 39 2023-09-02 criteria provided, single submitter clinical testing

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