ClinVar Genomic variation as it relates to human health

The AHI1 c.1765C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1 , PP1, PS3 , PP3, PM2. Based on this evidence we have classified this variant as Pathogenic.

The homozygous p.Arg589Ter variant in AHI1 was identified by our study in 2 family members with Joubert syndrome 3. The variant has been reported in 1 individual of African ethnicity with Joubert syndrome 3 (PMID: 16453322), and has been identified in 0.007% (1/15378) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267606641). 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: 2014) as pathogenic by GeneDx and OMIM. Animal models in zebrafish have shown that this variant causes Joubert syndrome 3 (PMID: 28118669). This nonsense variant leads to a premature termination codon at position 589, which is predicted to lead to a truncated or absent protein. Loss of function of the AHI1 gene is an established disease mechanism in autosomal recessive Joubert syndrome 3. The presence of this variant in 2 affected homozygotes, and in 2 individuals with Joubert syndrome 3 increases the likelihood that the p.Arg589Ter variant is pathogenic (PMID: 16453322). In summary, this variant meets criteria to be classified as pathogenic for Joubert syndrome 3 in an autosomal recessive manner based on the predicted impact of the variant, its low frequency in control populations, and multiple homozygous occurrences in individuals with Joubert syndrome 3. ACMG/AMP Criteria applied: PVS1, PS3, PM2, PM3 (Richards 2015).

Published functional studies in a zebrafish model demonstrate shorter cone outer segments (Lessieur et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32404165, 16453322, 28118669)

A Homozygote Nonsense variant c.1765C>T in Exon 12 of the AHI1 gene that results in the amino acid substitution p.Arg589* was identified. The observed variant has a minor allele frequency of 0.0000% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 2014 as of 2022-05-16). The homozygous p.Arg589Ter variant in AHI1 was identified previously in patients with Joubert syndrome 3 (Valente, Enza Maria et al., 2006). Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Lessieur, Emma M et al., 2017). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

This sequence change creates a premature translational stop signal (p.Arg589*) 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 (rs267606641, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome-related disorders (PMID: 16453322). ClinVar contains an entry for this variant (Variation ID: 2014). 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.