Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP3
The NM_001134831.2(AHI1):c.2988del(p.Val997SerfsTer20) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,608,248 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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]
Uncertain significance, criteria provided, single submitter
clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Dec 26, 2019
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Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Jul 13, 2020
The p.Val997SerfsX20 variant in AHI1 has been reported in 1 compound heterozygous individual with Retinitis pigmentosa (Carss 2017 PMID: 28041643). It has also been identified in 0.478% (146/30560) of East Asian chromosomes, including one homozgyous observation, by gnomAD (http://gnomad.broadinstitute.org), which is too common for the rarity and severity of Joubert syndrome. This variant is also reported in ClinVar (Variation ID: 280290). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 997 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, due to conflicting evidence the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1, PM3, BS1. -
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jul 07, 2022
Variant summary: AHI1 c.2988delA (p.Val997SerfsX20) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have not been observed at our laboratory but have been reported in association with phenotypes of Joubert syndrome in the HGMD database. The variant allele was found at a frequency of 0.00059 in 248166 control chromosomes, predominantly at a frequency of 0.0048 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal estimated allele frequency for a pathogenic variant in AHI1 causing Joubert Syndrome And Related Disorders phenotype (0.0013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Furthermore, this variant is flagged as an annotation of dubious quality in the gnomAD database due to its presence in an exon that does not exhibit a pattern of conservation typical or a protein coding exon (PHYLOCSF_WEAK code in the gnomAD data). c.2988delA has been reported in the literature among numerous sequencing studies of individuals with a range of phenotypes overlapping the spectrum of Joubert Syndrome And Related Disorders (example, Inherited Retinal Disease, Carss_2017). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Joubert syndrome 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter
research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Jan 08, 2019
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Feb 13, 2017
The c.2988delA variant in the AHI1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2988delA variant causes a frameshift starting with codon Valine 997, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Val997SerfsX20. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2988delA variant was not observed in approximately 5900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2988delA as a pathogenic variant. -
Retinal dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter
clinical testing
Blueprint Genetics
Nov 13, 2017
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Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided
research
NIHR Bioresource Rare Diseases, University of Cambridge
Jan 01, 2015
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Familial aplasia of the vermis Benign:1
Likely benign, criteria provided, single submitter