ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.5399G>A (p.Trp1800Ter)

gnomAD frequency: 0.00001  dbSNP: rs1553299079
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672460 SCV000797566 pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2018-01-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074797 SCV001240394 pathogenic Retinal dystrophy 2019-07-03 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001091135 SCV001247004 pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV002272322 SCV002556744 pathogenic Usher syndrome type 2A 2022-04-07 criteria provided, single submitter clinical testing The USH2A c.5399G>A variant is classified as PATHOGENIC (PVS1, PS4, PM3) The USH2A c.5399G>A variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 1800 (PVS1). The variant has been reported in several individuals with a clinical presentation of Usher syndrome, type 2A (PMID:24944099; 32531858) (PS4). This variant has been detected in trans with another pathogenic variant for this recessive condition in both this individual and in other reported cases in the literature (PM3). This variant is in dbSNP (rs1553299079) and has been reported in population databases (gnomAD 2/152142 allelels, no homozygotes. This variant has been reported in ClinVar as pathogenic for Usher syndrome and retinal dystrophy by other diagnostic laboratories (ClinVar Variation ID: 556449) and as damaging for Usher syndrome 2 in the disease database HGMD (CM149920).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002469251 SCV002766561 pathogenic Usher syndrome 2022-11-08 criteria provided, single submitter clinical testing Variant summary: USH2A c.5399G>A (p.Trp1800X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250992 control chromosomes (gnomAD). c.5399G>A has been reported in the literature in individuals affected with Usher Syndrome and Retinitis Pigmentosa (Baux_2014, Lenarduzzi_2015, Weisschuh_2020, Mansard_2021). Multiple patients were reported as compound heterozygous, carrying a second (likely) pathogenic variant, and at least one of which was confirmed in trans based on parental testing. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001091135 SCV003524080 pathogenic not provided 2023-07-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1800*) 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 Usher syndrome (PMID: 24944099, 25575603). ClinVar contains an entry for this variant (Variation ID: 556449). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV003453347 SCV004181813 pathogenic Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002272322 SCV004181815 pathogenic Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV003453347 SCV004206289 pathogenic Retinitis pigmentosa 39 2023-03-15 criteria provided, single submitter clinical testing

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