ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.13422C>G (p.Ile4474Met)

gnomAD frequency: 0.00001  dbSNP: rs1453273341
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001315227 SCV001505791 uncertain significance not provided 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 4474 of the USH2A protein (p.Ile4474Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of an inherited retinal dystrophy (PMID: 32037395). ClinVar contains an entry for this variant (Variation ID: 1016248). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. 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.
GeneDx RCV001315227 SCV002599996 uncertain significance not provided 2022-05-06 criteria provided, single submitter clinical testing Observed with a second USH2A variant, both in the homozygous state, in a patient with retinal degeneration in published literature (Zampaglione et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32037395)
Fulgent Genetics, Fulgent Genetics RCV002476463 SCV002782018 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2021-07-29 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003449896 SCV004183172 uncertain significance Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001830290 SCV004183173 uncertain significance Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV001830290 SCV002088264 uncertain significance Usher syndrome type 2A 2021-03-19 no assertion criteria provided clinical testing

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