ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.2168G>A (p.Arg723Gln) (rs121434351)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000002092 SCV000256255 pathogenic Joubert syndrome 3 2015-02-23 criteria provided, single submitter research
Invitae RCV000463110 SCV000547169 pathogenic Joubert syndrome 2020-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 723 of the AHI1 protein (p.Arg723Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs121434351, ExAC 0.009%). This variant has been observed in individual(s) with Joubert syndrome (PMID: 16453322, 26092869, Invitae). This variant has been reported to affect AHI1 protein function (PMID: 21623382). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics RCV000002092 SCV000803621 likely pathogenic Joubert syndrome 3 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Joubert syndrome, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:21623382).
GeneDx RCV001582460 SCV001812010 pathogenic not provided 2021-03-03 criteria provided, single submitter clinical testing Published functional studies demonstrate R723Q fails to localize to the primary cilium compared to the wild-type protein (Lancaster et al., 2011); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16453322, 31589614, 25217387, 31202121, 21623382, 26092869, 26354092)
OMIM RCV000002092 SCV000022250 pathogenic Joubert syndrome 3 2006-03-01 no assertion criteria provided literature only
Laboratory of Genetics in Ophthalmology,Institut Imagine RCV001172382 SCV001335440 pathogenic Joubert syndrome with ocular defect no assertion criteria provided research

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