ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.13732A>G (p.Lys4578Glu)

gnomAD frequency: 0.00003  dbSNP: rs765354805
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Total submissions: 7
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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 RCV000217262 SCV000272890 uncertain significance not specified 2016-04-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Lys4578Glu va riant in USH2A has not been previously reported in individuals with hearing loss or Usher syndrome, but has been identified in 4/11568 of Latino chromosomes and 3/66732 of European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs765354805). The lysine (Lys) at position 457 8 is not conserved in mammals or evolutionarily distant species and 2 mammals (c ape elephant shrew and opossum) carry a glutamic acid (Glu) at this position, ra ising the possibility that this change may be tolerated. Additional computationa l prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Lys4578Glu varian t is uncertain, its presence in mammals suggests that it is more likely to be be nign.
Blueprint Genetics RCV001074937 SCV001240544 uncertain significance Retinal dystrophy 2017-06-09 criteria provided, single submitter clinical testing
Invitae RCV001853496 SCV002186478 uncertain significance not provided 2022-07-06 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4578 of the USH2A protein (p.Lys4578Glu). This variant is present in population databases (rs765354805, gnomAD 0.02%). 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: 229620). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Fulgent Genetics, Fulgent Genetics RCV002485408 SCV002780315 uncertain significance Usher syndrome type 2A; Retinitis pigmentosa 39 2021-08-13 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003454603 SCV004183136 uncertain significance Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001833219 SCV004183137 uncertain significance Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV001833219 SCV002088248 uncertain significance Usher syndrome type 2A 2019-11-11 no assertion criteria provided clinical testing

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