ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.3187_3188del (p.Gln1063fs) (rs886039450)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254923 SCV000339777 pathogenic not provided 2016-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000254923 SCV000321997 pathogenic not provided 2016-08-15 criteria provided, single submitter clinical testing The c.3187_3188delCA pathogenic variant in the USH2A gene has been reported previously in association with Usher syndrome and retinitis pigmentosa (Seyedahmadi et al., 2004; Zhao et al., 2015). The c.3187_3188delCA variant causes a frameshift starting with codon Glutamine 1063, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 15 of the new reading frame, denoted p.Gln1063SerfsX15. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3187_3188delCA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3187_3188delCA as a pathogenic variant.
Invitae RCV000254923 SCV000957219 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1063Serfs*15) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another USH2A variant in individuals affected with Usher syndrome type 2 or retinitis pigemntosa (PMID: 23924366, 25472526). ClinVar contains an entry for this variant (Variation ID: 265288). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000594585 SCV000709745 pathogenic Usher syndrome 2018-03-07 criteria provided, single submitter clinical testing The p.Gln1036fs variant in USH2A has been reported in >5 individuals with Usher syndrome or retinitis pigmentosa (RP), all of whom were homozygous or compound heterozygous (Sandberg 2008, Le Quesne Stabej 2012, Steele-Stallard 2013, Zhao 2015, Carrigan 2016, LMM data). It has also been identified in 1/8732 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1063 and leads to a premature termination codon 15 amino acids downstream. This alteration is then 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. ACMG/AMP Criteria applied: PVS1; PMS3_VeryStrong.

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