ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.1859G>T (p.Cys620Phe) (rs758571672)

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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 RCV001171545 SCV001334332 likely pathogenic Usher syndrome 2020-02-25 reviewed by expert panel curation The c.1859G>T (p.Cys620Phe) variant has been observed in 0.000015% (5/129062) of non-Finnish European alleles in gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2). This variant has been observed in at least 2 individuals with other pathogenic or suspected-pathogenic variants (PM3_Strong; PMID: 22135276). Both patients identified with this variant displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID:22135276). A functional study was published that did not meet standards to count PS3 (PMID:16114888). The REVEL computational prediction analysis tool produced a score of 0.974, 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 the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3_Strong, PP4, PP3).
Counsyl RCV000664581 SCV000788568 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-05-18 criteria provided, single submitter clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761343 SCV000891329 likely pathogenic Usher syndrome, type 2A 2016-10-05 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000761343 SCV001156374 pathogenic Usher syndrome, type 2A 2019-02-01 criteria provided, single submitter clinical testing
Invitae RCV001208650 SCV001380051 pathogenic not provided 2020-09-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 620 of the USH2A protein (p.Cys620Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs758571672, ExAC 0.003%). This variant has been observed in several individuals affected with Usher syndrome (PMID: 22135276, 16963483, Invitae). ClinVar contains an entry for this variant (Variation ID: 549981). This variant has been reported to affect USH2A protein function (PMID: 16114888). This variant disrupts the p.Cys620 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 24944099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001171545 SCV001652947 likely pathogenic Usher syndrome 2020-06-19 criteria provided, single submitter clinical testing The p.Cys620Phe variant in USH2A has been reported in at least 2 individuals with Usher syndrome, including two compound heterozygotes (Le Quesne Stabej 2012). It has also been reported in ClinVar (Variation ID 549981). The p.Cys620Phe variant has been identified in 0.004% (5/129062) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant at the same position, p.Cys620Tyr has been reported in a homozygous individual with Usher syndrome (Baux 2014). In addition, an in vitro functional study suggests that this variant results in a failure of the Usherin peptide to co-immunoprecipitate fibronectin, which may indicate a disruption of normal protein function (Bhattacharya 2005); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses also suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PP4, PS3_Supporting.

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