ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.1876C>T (p.Arg626Ter)

gnomAD frequency: 0.00001  dbSNP: rs534534437
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000599059 SCV000701902 pathogenic not provided 2016-10-04 criteria provided, single submitter clinical testing
GeneDx RCV000599059 SCV000709899 pathogenic not provided 2021-08-30 criteria provided, single submitter clinical testing Nonsense 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 33090715, 33576794, 31266775, 10729113, 25649381, 29625443, 28559085, 29588463, 15823922, 27318125, 10909849, 25525159, 26338283, 15025721, 27460420, 21686329, 15325563, 18665195)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000592080 SCV000710847 pathogenic Usher syndrome 2019-03-19 criteria provided, single submitter clinical testing The p.Arg626X variant in USH2A has been reported >15 individuals with Usher syndrome, at least 9 of whom were homozygous or compound heterozygous with a second pathogenic USH2A variant on the other allele, and segregated in the compound heterozygous state in one affected relative (Weston 2000, Ouyang 2004, Seyedahmadi 2004, Ebermann 2009, Xu 2011, Jiang 2015, Lenassi 2015, Bonnet 2016). This variant has also been identified in 0.006% (7/113672) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 626, which is predicted to lead to a truncated or absent protein. Loss of function of the USH2A gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic USH2A variants in individuals with Usher syndrome. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1, PM2, PP1.
Invitae RCV000599059 SCV000959652 pathogenic not provided 2024-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg626*) 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 (rs534534437, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with USH2A-related conditions (PMID: 10729113, 15823922, 21686329, 25649381). ClinVar contains an entry for this variant (Variation ID: 497414). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074303 SCV001239876 pathogenic Retinal dystrophy 2019-06-19 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376324 SCV001573431 pathogenic Retinitis pigmentosa 39 2021-04-08 criteria provided, single submitter research The USH2A c.1876C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814193 SCV001755357 pathogenic Ear malformation 2021-07-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000599059 SCV002020851 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001271237 SCV002767837 pathogenic Usher syndrome type 2A 2020-10-19 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, 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 Usher syndrome (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 (7 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with Usher syndrome (MIM#276901) and Retinitis pigments (MIM#613809) (ClinVar, PMID: 27460420). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV002506407 SCV002816402 pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2022-01-05 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001376324 SCV004182492 pathogenic Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001271237 SCV004182493 pathogenic Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV001376324 SCV004207687 pathogenic Retinitis pigmentosa 39 2023-10-31 criteria provided, single submitter clinical testing
Natera, Inc. RCV001271237 SCV001452253 pathogenic Usher syndrome type 2A 2020-09-16 no assertion criteria provided clinical testing

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