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

gnomAD frequency: 0.00003  dbSNP: rs121434351

Total submissions: 8

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	Familial aplasia of the vermis	2024-01-20	criteria provided, single submitter	clinical testing	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.
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	2023-08-01	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); 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)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000002092	SCV002507012	uncertain significance	Joubert syndrome 3	2022-05-04	criteria provided, single submitter	curation	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).
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
Neurology Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University	RCV000002092	SCV003803086	uncertain significance	Joubert syndrome 3		no assertion criteria provided	clinical testing