ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.5516T>A (p.Val1839Glu) (rs886039867)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171534 SCV001334319 uncertain significance Usher syndrome 2020-02-25 reviewed by expert panel curation The c.5516T>A (p.Val1839Glu) variant in USH2A was absent from gnomAD v2.1.1 and present in 0.001549% (1/64578) of non-Finnish European chromosomes in gnomAD v3 (PM2). This variant has been identified in at least 1 proband with Usher syndrome (PMID: 28944237). In this individual, the p.Val1839Glu variant was detected in trans with a known pathogenic variant (PM3). This patient displayed both retinal degradation and sensorineural hearing loss, features highly specific for USH2A (PP4). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3, PP4.
Blueprint Genetics RCV001075572 SCV001241199 pathogenic Retinal dystrophy 2019-01-09 criteria provided, single submitter clinical testing
Invitae RCV001240204 SCV001413130 uncertain significance not provided 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces valine with glutamic acid at codon 1839 of the USH2A protein (p.Val1839Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with sensorineural hearing loss and retinitis pigmentosa (PMID: 28944237, Invitae). ClinVar contains an entry for this variant (Variation ID: 265979). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000256390 SCV000323137 uncertain significance Usher syndrome, type 2A no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000678635 SCV000804723 pathogenic Retinitis pigmentosa 39 2016-09-01 no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV001240204 SCV001920648 uncertain significance not provided no assertion criteria provided clinical testing

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