Submissions for variant NM_206933.4(USH2A):c.1111_1112del (p.Ile371fs)

dbSNP: rs1366496013

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000588348	SCV000693911	pathogenic	Usher syndrome type 2A	2017-06-25	criteria provided, single submitter	research	Reportedly 1 case with this variant in the supplement but that is not available at the time of review (broken link). In trans to a known pathogenic variant. In gnomAD, not found in exomes, once in genomes (1/30960 chromosomes). (PM2, PM3, PVS1).
Counsyl	RCV000668783	SCV000793437	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-08-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804948	SCV000944888	pathogenic	not provided	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile371Phefs*3) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 18641288). ClinVar contains an entry for this variant (Variation ID: 495336). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000804948	SCV001167832	pathogenic	not provided	2018-06-04	criteria provided, single submitter	clinical testing	The c.1111_1112delAT variant in the USH2A gene has been reported previously in association with Usher syndrome (Sandberg et al., 2008). The c.1111_1112delAT variant causes a frameshift starting with codon Isoleucine 371, changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Ile371PhefsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1111_1112delAT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1111_1112delAT as a pathogenic variant.
Blueprint Genetics	RCV001073236	SCV001238772	likely pathogenic	Retinal dystrophy	2018-08-09	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000588348	SCV002556437	pathogenic	Usher syndrome type 2A	2022-05-23	criteria provided, single submitter	clinical testing	The USH2A c.1111_1112del variant is classified as PATHOGENIC (PVS1, PM2, PS4_S) This variant is a deletion of two consecutive nucleotides in exon 6/72 of the USH2A gene, predicted to encode a frame shift of the mature mRNA with consequent premature termination of protein synthesis at codon 3 of the frame-shift, or 373 (USH2A:p.(Ile371PhefsTer3)) (PVS1). The variant has been identified in multiple unrelated individuals with Usher syndrome and non-syndromic Retinitis pigmentosa, and confirmed in trans with a second pathogenic variant in an individual with non-syndromic Retinitis pigmentosa (PMID:16963483, PMID:32176120, PMID:18641288). The variant is in dbSNP (rs1366496013) but it is rare in population databases (gnomAD: 1/152208, 0 homozygote) (PM2). This variant has been reported in ClinVar (VariationID: 495336) and HGMD (Accession: CD071406) as disease causing variant (PS4_S).
Genome-Nilou Lab	RCV003451325	SCV004182908	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000588348	SCV004182909	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003451325	SCV004208261	pathogenic	Retinitis pigmentosa 39	2023-09-14	criteria provided, single submitter	clinical testing