ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.2173T>C (p.Trp725Arg)

dbSNP: rs863225144
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program, University of Washington RCV000201537 SCV000256271 pathogenic Joubert syndrome 3 2015-02-23 criteria provided, single submitter research
Invitae RCV000817125 SCV000957670 uncertain significance Familial aplasia of the vermis 2021-10-13 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 725 of the AHI1 protein (p.Trp725Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 16155189, 26092869). ClinVar contains an entry for this variant (Variation ID: 217545). 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"). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV003237762 SCV002010698 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235125 SCV003933960 uncertain significance not specified 2023-05-11 criteria provided, single submitter clinical testing Variant summary: AHI1 c.2173T>C (p.Trp725Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248926 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2173T>C has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders (example:Bachman-Gagescu_2015 and Parisi_2006). 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: 26092869, 30055837, 17377524, 28125082). Three submitters have evaluated this variant and submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

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