Submissions for variant NM_206933.4(USH2A):c.5614delinsTTAACTTGGCAT (p.Ala1872fs)

dbSNP: rs869312180

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001073289	SCV001238826	pathogenic	Retinal dystrophy	2022-02-28	criteria provided, single submitter	clinical testing	Literature review and variant seen in at least 2 patients with a second likely pathogenic/pathogenic variant in trans.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386897	SCV001587295	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1872Leufs*64) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of USH2A-related conditions (PMID: 26872967). ClinVar contains an entry for this variant (Variation ID: 1069610). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272177	SCV002557945	pathogenic	Retinitis pigmentosa 39	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809) and Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (1 heterozygote, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported three times as pathogenic or likely pathogenic in ClinVar. It has also been reported in a patient with congenital/prelingual sensorineural hearing loss and retinitis pigmentosa (classic USH2) where a second loss-of-function variant was also identified on the other allele (PMID: 32176120). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001386897	SCV003840647	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26872967, 22135276, 31836858, 32176120)
Genome-Nilou Lab	RCV002272177	SCV004181785	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000210302	SCV005200886	pathogenic	Usher syndrome type 2A	2024-06-18	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210302	SCV000259085	likely pathogenic	Usher syndrome type 2A	2015-03-03	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001824687	SCV002075101	not provided	USH2A-related disorder		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-11-2020 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.