ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.7524del (p.Arg2509fs) (rs751176116)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000616874 SCV000731795 pathogenic Rare genetic deafness 2017-08-03 criteria provided, single submitter clinical testing The p.Arg2509fs variant in USH2A has been reported in the compound heterozygous state in at least two individuals with Usher syndrome (Bonnet 2011, Krawitz 2014 , Bonnet 2016). It has been identified in 1/111126 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs7 51176116). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency for Us her syndrome. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2509 and leads to a prematur e termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function is an established di sease mechanism for autosomal recessive Usher syndrome. In summary, the p.Arg25 09fs variant meets criteria to be classified as pathogenic for autosomal recessi ve Usher syndrome based on the predicted impact of the variant and compound hete rozygosity with other pathogenic USH2A variants in individuals with Usher syndro me.
Counsyl RCV000665082 SCV000789143 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-01-25 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073531 SCV001239078 pathogenic Retinal dystrophy 2019-05-11 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195909 SCV001366333 pathogenic Abnormality of the eye; Hearing loss 2019-03-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195922 SCV001366346 pathogenic Rare genetic syndrome 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PM4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199006 SCV001370001 pathogenic Abnormality of the eye 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. This variant was detected in heterozygous state.
Invitae RCV001202128 SCV001373230 pathogenic not provided 2019-11-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2509Glyfs*19) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751176116, ExAC 0.002%). This variant has been observed in individuals affected with Usher syndrome (PMID: 21569298, 27957503, 27460420, 25333064). ClinVar contains an entry for this variant (Variation ID: 517494). 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.

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