ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12874A>G (p.Asn4292Asp) (rs397517984)

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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 RCV001252674 SCV001428433 uncertain significance Usher syndrome 2020-07-28 reviewed by expert panel curation The c.12874A>G (p.Asn4292Asp) variant in USH2A was present in 0.01% (7/30616) of South Asian alleles in gnomAD v2.1.1 and was absent from gnomAD v3 (PM2_Supporting). It has been identified in the homozygous state in 1 proband with retinitis pigmentosa and segregated with disease in 2 additional family members (PM3_Supporting; PP1_Moderate; PMID: 25133751). The p.Asn4292Asp variant has also been identified in a proband with Hearing loss and Retinitis pigmentosa who carried a variant of uncertain significance in OTOF (SCV000065428.6). Finally, a patient with Retinitis pigmentosa carried a second variant of unknown significance in USH2A with phase unknown (PMID: 28041643, ClinVar ID: 438010). The REVEL computational prediction analysis tool produced a score of 0.707, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : PM2_Supporting, PM3_Supporting, PP1_Moderate, PP3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041732 SCV000065428 uncertain significance not specified 2012-01-16 criteria provided, single submitter clinical testing The Asn4292Asp variant in USH2A has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong supp ort for or against pathogenicity.
Counsyl RCV000666345 SCV000790621 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-03-30 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075301 SCV001240918 pathogenic Retinal dystrophy 2017-11-28 criteria provided, single submitter clinical testing
Invitae RCV001231366 SCV001403886 likely pathogenic not provided 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 4292 of the USH2A protein (p.Asn4292Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs397517984, ExAC 0.02%). This variant has been observed in individual(s) with retinitis pigmentosa (PMID: 25133751, 28041643, Invitae). ClinVar contains an entry for this variant (Variation ID: 48409). 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 C1). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 5
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504620 SCV000598780 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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