ClinVar Miner

Submissions for variant NM_001329943.3(KIAA0586):c.392del (p.Arg131fs) (rs534542684)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000186590 SCV000256428 pathogenic Joubert syndrome 23 2015-09-01 criteria provided, single submitter research
GeneDx RCV000255927 SCV000321807 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The c.428delG variant in the KIAA0586 gene has been reported previously in the homozygous or compound heterozygous state in several individuals with Joubert syndrome (Bachmann-Gagescu et al., 2015, Akawi et al., 2015; Stephen et al., 2015). This variant causes a frameshift starting with codon Arginine 143, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Arg143LysfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.428delG variant is observed in 73/9048 alleles (0.81%) from individuals of Ashkenazi Jewish background, and 769/246,736 global alleles (0.31%), in large population cohorts (Lek et al., 2016). Two individuals were reported to be homozygous for c.428delG in the gnomAD dataset, though clinical correlation and confirmation of this variant by an orthogonal sequencing method are not provided (Lek et al., 2016). Therefore, we interpret c.428delG as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255927 SCV000336030 pathogenic not provided 2017-06-08 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000255927 SCV000510710 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000612898 SCV000712155 pathogenic Joubert syndrome 2016-06-07 criteria provided, single submitter clinical testing The p.Arg143LysfsX4 variant in KIAA0586 has been reported in more than 20 indivi duals with Joubert syndrome in the compound heterozygous or homozygous state and is considered to be the most frequent pathogenic variant in the gene (Akawi 201 5, Bachmann-Gagescu-2015, Roosing 2015, Stephen 2015). This variant has been ide ntified in 0.49% (578/117798) of European chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs534542684). Although this variant has been seen in the general population, its frequency is low enou gh to be consistent with a recessive carrier frequency. This variant is predicte d to cause a frameshift, which alters the protein?s amino acid sequence beginnin g at position 143 and leads to a premature termination codon 4 amino acids downs tream. This alteration is then predicted to lead to a truncated or absent protei n. In summary, this variant meets criteria to be classified as pathogenic for Jo ubert syndrome in an autosomal recessive manner based upon segregation studies, predicted functional impact and lower frequency in controls. ACMG/AMP Criteria a pplied: PVS1_Strong, PM3_Strong.
Invitae RCV000652578 SCV000774448 pathogenic Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly 2018-09-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg143Lysfs*4) in the KIAA0586 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported to segregate with a relatively mild form of Joubert syndrome in ~2-5% of tested Joubert syndrome families (PMID: 26026149, 26437029, 26096313, 26386247). In the majority of these families, this variant was compound heterozygous with a second null variant. ClinVar contains an entry for this variant (Variation ID: 204593). Experimental studies have confirmed that this frameshift variant results in nonsense mediated decay (NMD) and an absent protein in cells from an affected individual (PMID: 26026149). Loss-of-function variants in KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000186590 SCV000782667 pathogenic Joubert syndrome 23 2017-06-02 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000186590 SCV000784496 pathogenic Joubert syndrome 23 2018-03-05 criteria provided, single submitter clinical testing
OMIM RCV000186590 SCV000240166 pathogenic Joubert syndrome 23 2015-06-11 no assertion criteria provided literature only

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