ClinVar Miner

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

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Total submissions: 19
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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, http://gnomad.broadinstitute.org; 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 2019-12-12 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
Mendelics RCV000186590 SCV001139469 pathogenic Joubert syndrome 23 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000186590 SCV001150142 pathogenic Joubert syndrome 23 2018-03-15 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073225 SCV001238761 pathogenic Retinal dystrophy 2018-08-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255927 SCV001246880 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000652578 SCV001251483 likely pathogenic Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly criteria provided, single submitter research This variant has been reported in Joubert syndrome and in cases with overlapping features of Jeune syndrome, or short-rib thoracic dysplasia with polydactyly. The c.428delG variant is considered a mild or hypomorphic variant that only causes disease when inherited in trans with a more severe KIAA0586 mutation (PMID: 29068549; 28125082; 26026149; 26096313; 26386044, 26386247; 30120217).
Integrated Genetics/Laboratory Corporation of America RCV001193558 SCV001362462 pathogenic Joubert Syndrome and Related Disorders 2019-11-13 criteria provided, single submitter clinical testing Variant summary: KIAA0586 c.428delG (p.Arg143LysfsX4) 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. The variant allele was found at a frequency of 0.0031 in 217674 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in KIAA0586 causing Joubert syndrome and related disorders phenotype (0.001). c.428delG has been reported in the literature in multiple individuals affected with Joubert syndrome (JB) in both compound heterozygous and homozygous state (e.g. Bachmann-Gagescu_2015, Pauli_2019, Roosing_2015). However, this variant was also found in healthy individuals in homozygous state in the literature (e.g.Pauli_2019). Pauli_2019 reports that c.428delG represents JB only if present in compound heterozygous state with more severe KIAA0586 variant but not in a homozygous situation. They also state that if present in homozygous state, mutations in other ciliopathy genes may be necessary for disease manifestation. Overall, these data indicate that the variant is very likely to be associated with disease. RNA analysis from the healthy homozygous individual carrying the variant revealed that transcripts are still expressed and may elude the mechanism of nonsense-mediated decay (Pauli_2019). However, another study reports absence of protein in fibroblasts taken from compound heterozygous patients (Roosing_2015). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196758 SCV001367391 pathogenic Cryptorchidism; Myopathy; Neonatal hypotonia 2019-11-21 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197828 SCV001368608 pathogenic Global developmental delay; Failure to thrive; Abnormal facial shape; Generalized hypotonia 2020-04-02 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_Mod,PM2. This variant was detected in heterozygous state.
OMIM RCV000186590 SCV000240166 pathogenic Joubert syndrome 23 2015-06-11 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000612898 SCV001142441 pathogenic Joubert syndrome 2020-01-06 no assertion criteria provided curation NM_001244189.1:c.428delG in the KIAA0586 gene has an allele frequency of 0.008 in Ashkenazi Jewish subpopulation in the gnomAD database.This variant is located in the 3rd exon (a total of 34 exons in the NM_001244189.1 transcript), therefore, it predicted to result in nonsense-mediated mRNA decay. It was detected in multiple individuals with autosomal recessive Joubert syndrome, compound heterozygous with c.2512C>T (p.Arg838*), c.1413-1G>C, respectively (PMID: 26386247; 26096313).Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PM3_Strong.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003979 SCV001162005 likely pathogenic Congenital cerebellar hypoplasia; Rod-cone dystrophy; Intellectual disability no assertion criteria provided research

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