ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.4510dup (p.Arg1504fs) (rs727503731)

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Total submissions: 9
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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, Partners HealthCare 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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000412947 SCV000337028 pathogenic not provided 2015-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000412947 SCV000490870 pathogenic not provided 2016-06-15 criteria provided, single submitter clinical testing The c.4510dupA pathogenic variant in the USH2A gene has been reported previously in association with Usher syndrome (please note that in some publications this variant is reported as c.4510_4511insA or c.4510_11insA) (Weston et al., 2000; Seyedahmadi et al., 2004; Le Quesne Stabej et al., 2012). The deletion causes a frameshift starting with codon Arginine 1504, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Arg1504LysfsX26. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore we interpret this variant to be pathogenic.
Invitae RCV000412947 SCV001217207 pathogenic not provided 2019-12-17 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. 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 been observed in individuals affected with Usher syndrome (PMID: 22135276, 10729113, 15325563). ClinVar contains an entry for this variant (Variation ID: 166504). 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.
Blueprint Genetics RCV001074086 SCV001239655 pathogenic Retinal dystrophy 2018-12-27 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

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