Submissions for variant NM_001134831.2(AHI1):c.2174G>A (p.Trp725Ter)

gnomAD frequency: 0.00001  dbSNP: rs587783013

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000144464	SCV000256272	pathogenic	Joubert syndrome 3	2015-02-23	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV000144464	SCV000915147	likely pathogenic	Joubert syndrome 3	2017-10-17	criteria provided, single submitter	clinical testing	The AHI1 c.2174G>A (p.Trp725Ter) stop-gained variant has been reported in at least four studies and is found in a compound heterozygous state in three individuals with Joubert syndrome and in one individual with non-syndromic retinitis pigmentosa (RP) (Seong et al. 2015; Bachmann-Gagescu et al. 2015; Enokizono et al. 2017, Nguyen et al. 2017). All three individuals with Joubert syndrome carried null variants on the second allele and the individual with RP carried a missense variant on the second allele. Authors suggest individuals with one mild and one severe AHI1 variant will have remnant Jouberin activity that is sufficient for ciliary function in all cells except retinal photoreceptor cells (Nguyen et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000348 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of stop-gained variants, the p.Trp725Ter variant is classified as likely pathogenic for Joubert syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Vision Research, Yonsei University College of Medicine	RCV001262092	SCV001370768	pathogenic	Leber congenital amaurosis	2020-07-06	criteria provided, single submitter	clinical testing
Invitae	RCV003495112	SCV004294413	pathogenic	Familial aplasia of the vermis	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp725*) in the AHI1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AHI1 are known to be pathogenic (PMID: 15322546, 16453322, 28442542, 29186038). This variant is present in population databases (rs587783013, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome and/or retinitis pigmentosa (PMID: 28431631, 28442542). ClinVar contains an entry for this variant (Variation ID: 156382). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Laboratory, Seoul National University Hospital	RCV000144464	SCV000189598	pathogenic	Joubert syndrome 3	2014-09-18	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678521	SCV000804593	pathogenic	Retinitis pigmentosa	2016-09-01	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001698972	SCV001921644	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001698972	SCV001930362	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001698972	SCV001954328	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001698972	SCV001969293	pathogenic	not provided		no assertion criteria provided	clinical testing
Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University	RCV000144464	SCV003803087	uncertain significance	Joubert syndrome 3		no assertion criteria provided	clinical testing