ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.14453C>T (p.Pro4818Leu) (rs143344549)

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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, Partners HealthCare Personalized Medicine RCV000613330 SCV000710852 likely pathogenic Rare genetic deafness 2016-12-22 criteria provided, single submitter clinical testing The p.Pro4818Leu variant in USH2A has been reported in 5 individuals with Usher syndrome and 1 individual with retinitis pigmentosa (Aller 2006, Garcia-Garcia 2 011, Jaijo 2010, McGee 2010, Zhao 2015). Two individuals with Usher syndrome wer e confirmed to have a different truncating variant affecting the other copy of U SH2A. This variant has been identified in several populations by the Exome Aggre gation Consortium with the highest frequency of 3/16510 in South Asian chromosom es (ExAC, http://exac.broadinstitute.org; dbSNP rs143344549). However, this is low enough to be consistent with a recessive carrier frequency. Computational pr ediction tools and conservation analysis suggest that the p.Pro4818Leu variant m ay impact the protein. In summary, although additional studies are required to f ully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome based on its occurrence in trans with another pathogenic variant in USH2A in multiple unrelated affected individuals.
Mendelics RCV000986515 SCV001135530 likely pathogenic Usher syndrome, type 2A 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001040115 SCV001203673 pathogenic not provided 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 4818 of the USH2A protein (p.Pro4818Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs143344549, ExAC 0.02%). This variant has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17085681, 29899460, 22004887, 25472526). 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: 504509). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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