ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.1267C>T (p.Gln423Ter)

gnomAD frequency: 0.00013  dbSNP: rs777668842
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201715 SCV000256247 pathogenic Joubert syndrome 3 2015-02-23 criteria provided, single submitter research
Invitae RCV000206729 SCV000259658 pathogenic Joubert syndrome 2021-11-10 criteria provided, single submitter clinical testing 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.
GeneDx RCV000482493 SCV000567666 pathogenic not provided 2022-01-03 criteria provided, single submitter clinical testing 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)
Blueprint Genetics RCV001074545 SCV001240136 pathogenic Retinal dystrophy 2018-03-13 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000482493 SCV001247115 pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376375 SCV001573493 pathogenic Rod-cone dystrophy 2021-04-08 criteria provided, single submitter research 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.
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328119 SCV001449180 pathogenic Nephronophthisis 2018-05-03 no assertion criteria provided clinical testing 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.

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