Submissions for variant NM_007123.6(USH2A):c.4510dup (p.Arg1504fs)

dbSNP: rs727503731

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000710323	SCV000840511	pathogenic	Usher syndrome	2018-09-10	reviewed by expert panel	curation	The c.4510dupA (p.Arg1504LysX26) variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 21/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in 2 patients with hearing loss in trans with 2 different pathogenic variants (PM3_S; PMID:22135276). The allele frequency of the p.Arg1504LysX26 variant in the USH2A gene is 0.003% (3/111138) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). At least one patient with a variant in this gene displayed features of retinitis pigmentosa (PP4; PMID: 22135276). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_S, PM2, PP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152615	SCV000201920	pathogenic	Rare genetic deafness	2013-04-10	criteria provided, single submitter	clinical testing	The Arg1504fs variant in USH2A has been reported in five individuals with Usher syndrome, of which at least three were compound heterozygous with a second patho genic USH2A variant (Weston 2000, Le Quesne Stabej 2012, Seyedahmadi 2004). This frameshift variant is predicted to alter the protein?s amino acid sequence begi nning at position 1504 and lead to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent p rotein. In summary, this variant meets our criteria to be classified as pathogen ic (http://pcpgm.partners.org/LMM).
Eurofins Ntd Llc (ga)	RCV000412947	SCV000337028	pathogenic	not provided	2015-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000412947	SCV000490870	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Observed with a pathogenic variant in an unrelated patient in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Carss et al., 2017); 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 a significant frequency in large population cohorts (gnomAD); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000840511.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 22135276, 10729113, 15325563, 18641288, 28041643, 31980526, 32581362, 32037395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412947	SCV001217207	pathogenic	not provided	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1504Lysfs*26) 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 (rs727503731, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 10729113, 15325563, 22135276). ClinVar contains an entry for this variant (Variation ID: 166504). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074086	SCV001239655	pathogenic	Retinal dystrophy	2018-12-27	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505055	SCV001950424	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg1504LysfsTer26 variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP3, PP4. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Fulgent Genetics, Fulgent Genetics	RCV002498718	SCV002808914	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-04-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984232	SCV004208259	pathogenic	Retinitis pigmentosa 39	2024-03-25	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505055	SCV000598811	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000984231	SCV001132308	pathogenic	Usher syndrome type 2A	2017-02-16	no assertion criteria provided	clinical testing
Counsyl	RCV000984232	SCV001132309	pathogenic	Retinitis pigmentosa 39	2017-02-16	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984231	SCV001462267	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing