ClinVar Miner

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

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Total submissions: 5
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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: 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 likely pathogenic not provided 2019-11-11 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. 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.

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