ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.14531C>T (p.Thr4844Met)

gnomAD frequency: 0.00010  dbSNP: rs200570742
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000041766 SCV000065462 likely benign not specified 2015-08-04 criteria provided, single submitter clinical testing p.Thr4844Met in exon 66 of USH2A: This variant has been reported in the heterozy gous state in one individual with nonsyndromic retinitis pigmentosa, but a varia nt on the second allele was not identified (McGee 2010). It is not expected to h ave clinical significance due to a lack of conservation across species, includin g mammals. Of note, several mammals carry a methionine (Met) at this position de spite high nearby amino acid conservation. The p.Thr4844Met variant has also bee n identified in 4/11578 Latino chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs200570742).
GeneDx RCV001038994 SCV000714909 likely benign not provided 2020-11-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 20507924)
Invitae RCV001038994 SCV001202500 uncertain significance not provided 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4844 of the USH2A protein (p.Thr4844Met). This variant is present in population databases (rs200570742, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48443). 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. 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.

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