ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463110 SCV000547169 likely pathogenic Joubert syndrome 2016-12-05 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 reported to be homozygous in individuals with Joubert syndrome (PMID: 16453322, 26092869). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. An experimental study has shown that this missense change results in mislocalization of the AHI1 protein and decreased cellular response to Wnt signaling (PMID: 21623382). In summary, this variant is a rare missense change that disrupts protein function and has been reported in the homozygous state in individuals with Jourbert syndrome. These evidence indicate that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000002092 SCV000022250 pathogenic Joubert syndrome 3 2006-03-01 no assertion criteria provided literature only
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).
UW Hindbrain Malformation Research Program,University of Washington RCV000002092 SCV000256255 pathogenic Joubert syndrome 3 2015-02-23 criteria provided, single submitter research

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