ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.13374del (p.Glu4458fs) (rs727503715)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152565 SCV000201812 pathogenic Rare genetic deafness 2014-09-15 criteria provided, single submitter clinical testing The p.Glu4458fs variant in USH2A has been reported in four individuals with Ushe r syndrome, all of whom are compound heterozygous with a second pathogenic USH2A variant (Baux 2007, Stabej 2012). It has not been identified in large populat ion studies. This variant is predicted to cause a frameshift, which alters the p rotein?s amino acid sequence beginning at position 4458 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. In summary, this variant meets our crit eria to be classified as pathogenic for usher syndrome in an autosomal recessive manner (
GeneDx RCV000493634 SCV000582685 pathogenic not provided 2017-04-27 criteria provided, single submitter clinical testing The c.13374delA variant in the USH2 gene has been reported previously in the compound heterozygous state with a second USH2 variant in patients with Usher syndrome type II (Baux et al., 2007; Le Quesne Stabej et al., 2012). The c.13374delA variant causes a frameshift starting with codon Glutamic Acid 4458, changes this amino acid to a Aspartic Acid residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Glu4458AspfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.13374delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.13374delA as a pathogenic variant.
Invitae RCV000493634 SCV001198901 pathogenic not provided 2020-02-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu4458Aspfs*3) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727503715, ExAC 0.002%). This variant has been observed in individuals affected with USH2A-related conditions (PMID: 17405132, 28041643). ClinVar contains an entry for this variant (Variation ID: 166428). 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504893 SCV000598787 pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Counsyl RCV000666832 SCV000791190 pathogenic Retinitis pigmentosa 39 2017-05-01 no assertion criteria provided clinical testing

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