ClinVar Genomic variation as it relates to human health

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).

The homozygous p.Arg723Gln variant in AHI1 was identified by our study in 2 siblings with Joubert syndrome 3. The variant has been reported in 4 individuals of Italian and unknown ethnicity with Joubert syndrome 3 (PMID: 26092869, 31202121, 16453322, 26354092), and has been identified in 0.008% (3/35370) of Latino, 0.008% (2/24202) of African, and 0.003% (4/128110) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121434351). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 2015) as pathogenic by OMIM and UW Hindbrain Malformation Research Program, University of Washington, and as likely pathogenic by Invitae and SIB Swiss Institute of Bioinformatics. In vitro functional studies provide some evidence that the p.Arg723Gln variant may slightly impact protein function (PMID: 21623382). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in at least 2 affected homozygotes and in 2 individuals with Joubert syndrome 3 increases the likelihood that the p.Arg723Gln variant is pathogenic (PMID: 26092869, 31202121, 16453322). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PS3_supporting (Richards 2015).

Published functional studies demonstrate R723Q fails to localize to the primary cilium compared to the wild-type protein (Lancaster et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26354092, 16453322, 26092869, 31202121, 25217387, 31589614, 34448047, 15467982, 28442542, 34220074, 31069529, 21623382)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 723 of the AHI1 protein (p.Arg723Gln). This variant is present in population databases (rs121434351, gnomAD 0.009%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 16453322, 26092869; Invitae). ClinVar contains an entry for this variant (Variation ID: 2015). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AHI1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AHI1 function (PMID: 21623382). For these reasons, this variant has been classified as Pathogenic.

The AHI1 c.2168G>A variant is predicted to result in the amino acid substitution p.Arg723Gln. This variant has been reported in both the homozygous and compound heterozygous state in individuals with Joubert syndrome (Valente et al. 2006. PubMed ID: 16453322; Ganapathy et al. 2019. PubMed ID: 31069529; Perea-Romero et al. 2021. PubMed ID: 34448047; Bachmann-Gagescu et al. 2015. PubMed ID: 26092869; Altieri et al. 2019. PubMed ID: 31202121; Sharawat et al. 2021. PubMed ID: 34220074). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD. Functional studies indicate that the c.2168G>A (p.Arf723Gln) variant showed similar protein expression to wildtype protein in 293T cells and mouse inner medullary collecting duct cells, but failure to localize to the primary cilium compared to wildtype (Lancaster et al. 2011. PubMed ID: 21623382). This variant is interpreted as likely pathogenic.