ClinVar Miner

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

gnomAD frequency: 0.00347  dbSNP: rs534542684
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Total submissions: 35
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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 2023-10-12 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29453417, 30609409, 26026149, 26437029, 26386247, 28497568, 28832562, 30120217, 32381069, 32581362, 34426522, 34716235, 34611884, 26096313)
Eurofins Ntd Llc (ga) 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, Mass General Brigham Personalized Medicine RCV000612898 SCV000712155 pathogenic Familial aplasia of the vermis 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 2024-01-30 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. Loss-of-function variants in KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481, 26386044). This variant is present in population databases (rs534542684, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26026149, 26096313, 26386247, 26437029, 30120217). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204593). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic 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 Munich, Klinikum Rechts Der Isar, Tu München 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 Center for Human Genetics Tuebingen RCV000255927 SCV001246880 pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing KIAA0586: PVS1, PM3, PM2:Supporting
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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193558 SCV001362462 pathogenic Joubert syndrome and related disorders 2021-07-23 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 the compound heterozygous and homozygous state in multiple individuals affected with Joubert Syndrome And Related Disorders (e.g. Bachmann-Gagescu_2015, Roosing_2015, Pauli_2019, Sumathipala_2020). However, this variant was also found in healthy individuals in homozygous state in the literature (e.g. Pauli_2019). Pauli et al (2019) reports that c.428delG represents JB only if present in compound heterozygous state with a more severe KIAA0586 variant but not in a homozygous situation. They also state that if present in the 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). Seventeen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000186590 SCV001368608 pathogenic Joubert syndrome 23 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,PS1.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000255927 SCV001446644 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000186590 SCV001870370 pathogenic Joubert syndrome 23 2020-03-03 criteria provided, single submitter research ACMG codes:PVS1, PM3, PP5
Revvity Omics, Revvity Omics RCV000255927 SCV002023242 pathogenic not provided 2023-11-13 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000186590 SCV002059380 pathogenic Joubert syndrome 23 2017-01-13 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000652578 SCV002061501 pathogenic Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly 2021-08-18 criteria provided, single submitter clinical testing PVS1, PM3_strong
Genetic Services Laboratory, University of Chicago RCV000255927 SCV002064433 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing
New York Genome Center RCV000652578 SCV002097735 pathogenic Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly 2021-10-23 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000186590 SCV002579172 pathogenic Joubert syndrome 23 2022-05-23 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000186590 SCV004027798 pathogenic Joubert syndrome 23 2023-05-23 criteria provided, single submitter clinical testing Identified as compund heterozygous with NM_001329943.3:c.3142_3144+5del. Criteria applied: PVS1,PM3_VSTR
Preventiongenetics, part of Exact Sciences RCV003401022 SCV004103141 pathogenic KIAA0586-related condition 2023-07-09 criteria provided, single submitter clinical testing The KIAA0586 c.428delG variant is predicted to result in a frameshift and premature protein termination (p.Arg143Lysfs*4). This variant was reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive Joubert syndrome (Roosing et al. 2015. PubMed ID: 26026149; Bachmann-Gagescu et al. 2015. PubMed ID: 26096313; Stephen et al. 2015. PubMed ID: 26386247; Stark et al. 2017. PubMed ID: 28832562). However, this variant was reported in the homozygous state in a healthy mother and RNA analysis found that this variant escaped nonsense mediated decay (Pauli et al. 2018. PubMed ID: 30120217). It was suggested that this variant may only be causative when found in trans with a more severe pathogenic variant in KIAA0586, or found in the homozygous state with an additional hypomorphic variant in a different ciliopathy gene (Pauli et al 2018. PubMed ID: 30120217). This variant is reported in ~0.3% of alleles in gnomAD, including being found in the homozygous state in two individuals (https://gnomad.broadinstitute.org/variant/14-58899156-AG-A). Based on above information, this variant is interpreted as pathogenic.
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 Familial aplasia of the vermis 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
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV001283811 SCV001469208 likely pathogenic Short-rib thoracic dysplasia 14 with polydactyly 2020-09-10 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000255927 SCV001741665 pathogenic not provided no assertion criteria provided clinical testing
GeneReviews RCV000186590 SCV001792274 not provided Joubert syndrome 23 no assertion provided literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000255927 SCV001800402 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000255927 SCV001929223 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000255927 SCV001957601 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000255927 SCV001964839 pathogenic not provided no assertion criteria provided clinical testing

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