ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.12823T>A (p.Ser4275Thr) (rs138607917)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000215653 SCV000272889 uncertain significance not specified 2015-05-22 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ser4275Thr va riant in USH2A has previously been reported in one individual with Usher syndrom e and one individual with isolated retinitis pigmentosa; however, a variant affe cting the remaining copy of USH2A was not identified in either individual (Le Qu esne Stabej 2012, Wang 2014). This variant has been reported in 0.1% (48/66670) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs138607917); however, this frequency is not high enoug h to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ser4275Thr variant is unce rtain, the available frequency data suggests that it is more likely to be benign .
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726657 SCV000701989 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000726657 SCV000884863 uncertain significance not provided 2018-04-12 criteria provided, single submitter clinical testing The USH2A: p.Ser4275Thr variant (rs138607917) was reported in one individual from a cohort of patients with inherited eye disease subject to genetic testing (Haer-Wigman 2017). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.09 percent in the European non-Finnish population (identified on 119 out of 126,332 chromosomes) and has been reported to the ClinVar database (Variation ID: 229619). The serine at position 4275 is moderately conserved considering 12 species (Alamut v2.11) and computational analyses of the effects of the p.Ser4275Thr variant on protein structure and function provide conflicting results (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ser4275Thr variant with certainty.
Athena Diagnostics Inc RCV000726657 SCV001146600 uncertain significance not provided 2018-12-31 criteria provided, single submitter clinical testing
Invitae RCV000726657 SCV001413500 uncertain significance not provided 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 4275 of the USH2A protein (p.Ser4275Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs138607917, ExAC 0.07%). This variant has been observed as heterozygous in an individual affected with retinitis pigmentosa (PMID: 28224992). This variant has also been observed in unaffected controls (PMID: 22135276). ClinVar contains an entry for this variant (Variation ID: 229619). 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: "Benign"; Align-GVGD: "Class C55"). 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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