ClinVar Miner

Submissions for variant NM_001134831.2(AHI1):c.910dup (p.Thr304fs) (rs753874898)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201689 SCV000256261 pathogenic Joubert syndrome 3 2015-02-23 criteria provided, single submitter research
Invitae RCV001226946 SCV001399278 pathogenic Joubert syndrome 2019-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr304Asnfs*6) in the AHI1 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with clinical features of Joubert syndrome (PMID: 16453322, 28431631). This variant is also known as c.903insA and c.903_910insA in the literature. Loss-of-function variants in AHI1 are known to be pathogenic (PMID: 15322546, 16453322). For these reasons, this variant has been classified as Pathogenic.
Breda Genetics srl RCV000201689 SCV001422498 pathogenic Joubert syndrome 3 2020-07-15 criteria provided, single submitter clinical testing The variant c.910dupA (p.Thr304Asnfs*6) is reported as pathogenic for Joubert syndrome 3 in ClinVar (Variation ID: 217536). The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 6 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is present in gnomAD with an estimated allele frequency of 0.0001588, with no homozygous individuals reported. However, this variant was filtered out the gnomAD database because of it is found in a low complexity region and failed the random forest filters, due to presence of a poli-T stretch. Chafai-Elalaoui et al. (2015) reported the pathogenic variant c.910dupA (p.Thr304Asnfs*6) in the homozygous state in 3 affected sibling of a Moroccan family with Joubert syndrome (PMID: 26541515). The same mutation had already been reported by Kroes et al. (2008) in two Dutch patients in the compound heterozygous state (PMID: 18054307).

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