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

dbSNP: 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	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.
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-02-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000041829	SCV000487429	likely pathogenic	Usher syndrome type 2A	2016-08-18	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Counsyl	RCV000410392	SCV000487430	likely pathogenic	Retinitis pigmentosa 39	2016-08-18	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].