Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001134831.2(AHI1):c.1267C>T(p.Gln423Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,600,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
AHI1 (HGNC:21575): (Abelson helper integration site 1) This gene is apparently required for both cerebellar and cortical development in humans. This gene mutations cause specific forms of Joubert syndrome-related disorders. Joubert syndrome (JS) is a recessively inherited developmental brain disorder with several identified causative chromosomal loci. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-135455811-G-A is Pathogenic according to our data. Variant chr6-135455811-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-135455811-G-A is described in Lovd as [Pathogenic]. Variant chr6-135455811-G-A is described in Lovd as [Likely_pathogenic].
UW Hindbrain Malformation Research Program, University of Washington
Feb 23, 2015
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jul 01, 2017
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jan 03, 2022
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: 21866095, 26092869, 28492532, 25525159, 16453322, 16155189, 31963381, 31589614) -
Nephronophthisis Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead
May 03, 2018
This individual is heterozygous for the c.1267C>T and c.2246C>G variants in the AHI1 gene. Both variants create premature stop codons, p.Gln423*and p.Ser749* respectively, and may result in null alleles due to nonsense-mediated mRNA decay. To our knowledge, these variants have not been reported in population databases (dbSNP, ESP, ExAC) and have not been previously associated with disease. However, other truncating mutations downstream of these amino acids have been described in the literature (Parisi et al, J Med Genet. 2006; 43(4):334-339). Both the c.1267C>T and c.2246C>G variants are considered to be pathogenic according to ACMG guidelines. -
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 22, 2023
Variant summary: AHI1 c.1267C>T (p.Gln423X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanisms for disease. The variant allele was found at a frequency of 6.5e-05 in 229968 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AHI1 causing Joubert Syndrome And Related Disorders (6.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.1267C>T has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders (e.g. Bachmann-Gagescu_2015), including at least one compound heterozygous patient with another pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 26092869). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Rod-cone dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter
research
Ocular Genomics Institute, Massachusetts Eye and Ear
Apr 08, 2021
The AHI1 c.1267C>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: PM2, PVS1, PP1, PM3. Based on this evidence we have classified this variant as Pathogenic. -
Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 25, 2024
This sequence change creates a premature translational stop signal (p.Gln423*) 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 (rs777668842, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Joubert syndrome or Joubert syndrome-related disorders (PMID: 16155189, 16453322, 26092869). ClinVar contains an entry for this variant (Variation ID: 217523). For these reasons, this variant has been classified as Pathogenic. -