ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.11713C>T (p.Arg3905Cys) (rs368675850)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001252669 SCV001428428 likely pathogenic Usher syndrome 2020-06-24 reviewed by expert panel curation The c.11713C>T (p.Arg3905Cys) variant in USH2A was present in 0.03281% (1/3048) of South Asian chromosomes in gnomAD v3, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined for autosomal recessive hearing loss by the ClinGen Hearing Loss Expert Panel (PM2_Supporting; This variant has been reported in 3 individuals with Usher syndrome and a second pathogenic or likely pathogenic variant identified in USH2A, one of which was confirmed to be in trans with the p.Arg3905Cys variant (PM3_Strong; PMID: 28559085, 27208204, 31877679). At least one of these probands was confirmed to have both hearing loss and retinitis pigmentosa, features highly specific for Usher syndrome (PP4). The REVEL computational prediction tool produced a score of 0.8, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_Strong, PM2_Supporting, PP3, PP4.
GeneDx RCV000482491 SCV000565651 likely pathogenic not provided 2013-03-19 criteria provided, single submitter clinical testing The R3905C missense change in the USH2A gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. The R3905C amino acid substitution is non-conservative with positively charged residue (Arg) being replaced a neutral residue (Cys). Furthermore, the addition of a Cysteine residue may affect disulfide bonds. The residue at which this substitution occurs is well conserved within the fibronectin type III domain of the usherin protein. According to the Human Gene Mutation Database (HGMD) other missense mutations in neighboring residues (N3894G and G3895E) have been reported in association with Usher syndrome. The R3905C variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Therefore, R3905C is a strong candidate for a pathogenic variant, although the possibility that it is a benign variant cannot be excluded.
Counsyl RCV000675144 SCV000800740 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-03-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000482491 SCV001147667 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Invitae RCV000482491 SCV001222081 pathogenic not provided 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3905 of the USH2A protein (p.Arg3905Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs368675850, ExAC 0.01%). This variant has been observed in individual(s) with Usher syndrome (PMID: 24944099, 25333064, 27208204, 28559085). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 236537). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000225477 SCV001238874 pathogenic Retinal dystrophy 2018-11-22 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000225477 SCV000282647 uncertain significance Retinal dystrophy no assertion criteria provided clinical testing

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