Submissions for variant NM_001134831.2(AHI1):c.96dup (p.Leu33fs)

dbSNP: rs747322175

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778779	SCV000915149	uncertain significance	Joubert syndrome 3	2019-01-10	criteria provided, single submitter	clinical testing	The AHI1 c.96dupA (p.Leu33ThrfsTer9) variant results in a frameshift and is predicted to result in an absent or truncated protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Leu33ThrfsTer9 variant is reported at a frequency of 0.000044 in the European (non-Finnish) population of the Exome Aggregation Database. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for Joubert syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV001009216	SCV001169035	likely pathogenic	not provided	2019-01-14	criteria provided, single submitter	clinical testing	The c.96dupA variant in the AHI1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.96dupA variant causes a frameshift starting with codon Leucine 33, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Leu33ThrfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.96dupA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.96dupA as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003598005	SCV004474948	pathogenic	Familial aplasia of the vermis	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu33Thrfs*9) 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 (rs747322175, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with AHI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 631974). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics, Academic Medical Center	RCV001009216	SCV001922096	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001009216	SCV001962996	pathogenic	not provided		no assertion criteria provided	clinical testing