Submissions for variant NM_206933.4(USH2A):c.3547_3548del (p.Ile1183fs) (rs397518013)

Total submissions: 6

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	2019-01-30	reviewed by expert panel	curation	The p.Ile1183fs variant introduces a premature stop codon in biologically-relevant-exon 17/72 (NM_206933.2) that is predicted to lead to a truncated or absent protein in a gene wherein which loss-of-function is an established mechanism (PVS1; PMIDs: 9624053, 25211151, 20497194). The allele frequency of the p.Ile1183fs variant in USH2A is 0.0009% (1/111274) of non-Finnish European alleles in gnomAD , which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome type 2A based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PVS1, PM2).
Laboratory for Molecular Medicine, Partners HealthCare 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 Clinical Services Laboratory,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	2020-01-30	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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48503). Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). For these reasons, this variant has been classified as Pathogenic.