ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.7939C>T (p.Pro2647Ser)

dbSNP: rs1414367127
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001204893 SCV001376122 uncertain significance not provided 2022-06-20 criteria provided, single submitter clinical testing 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 936154). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2647 of the USH2A protein (p.Pro2647Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003331078 SCV004039440 uncertain significance not specified 2023-08-25 criteria provided, single submitter clinical testing Variant summary: USH2A c.7939C>T (p.Pro2647Ser) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251136 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7939C>T has been reported at a compound heterozygous state along with a frame-shifting pathogenic variant and another missense VUS variant in at-least one individual affected with Usher Syndrome (example, Columbo_2021 and 2022), however in other individuals affected with autosomal recessive retinitis pigmentosa or unspecified inherited retinal disease, it has been reported as a single heterozygous change, without a second disease-causing variant (example, Reurink_2023, Karali_2022). This variant, in cis along with c.14204C>G(p.Pro4735Arg) has been mentioned as a complex variant c.[14204C>G;7939C>T] (Karali_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34781295, 33576794, 36460718, 36785559). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (both uncertain significance). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV003449649 SCV004183190 uncertain significance Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001828644 SCV004183191 uncertain significance Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV001828644 SCV002090838 uncertain significance Usher syndrome type 2A 2020-01-29 no assertion criteria provided clinical testing

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