Total submissions: 35
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
UW Hindbrain Malformation Research Program, |
RCV000186590 | SCV000256428 | pathogenic | Joubert syndrome 23 | 2015-09-01 | criteria provided, single submitter | research | |
Gene |
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 |
RCV000255927 | SCV000336030 | pathogenic | not provided | 2017-06-08 | criteria provided, single submitter | clinical testing | |
Center for Pediatric Genomic Medicine, |
RCV000255927 | SCV000510710 | pathogenic | not provided | 2016-11-17 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular 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, |
RCV000186590 | SCV000782667 | pathogenic | Joubert syndrome 23 | 2017-06-02 | criteria provided, single submitter | clinical testing | |
Genomic Research Center, |
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, |
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 | |
Ce |
RCV000255927 | SCV001246880 | pathogenic | not provided | 2023-10-01 | criteria provided, single submitter | clinical testing | KIAA0586: PVS1, PM3, PM2:Supporting |
UNC Molecular Genetics Laboratory, |
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, |
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, |
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, |
RCV000255927 | SCV001446644 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Hudson |
RCV000186590 | SCV001870370 | pathogenic | Joubert syndrome 23 | 2020-03-03 | criteria provided, single submitter | research | ACMG codes:PVS1, PM3, PP5 |
Revvity Omics, |
RCV000255927 | SCV002023242 | pathogenic | not provided | 2023-11-13 | criteria provided, single submitter | clinical testing | |
Centogene AG - |
RCV000186590 | SCV002059380 | pathogenic | Joubert syndrome 23 | 2017-01-13 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
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, |
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, |
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, |
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, |
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, |
RCV001003979 | SCV001162005 | likely pathogenic | Congenital cerebellar hypoplasia; Rod-cone dystrophy; Intellectual disability | no assertion criteria provided | research | ||
Biochemical Molecular Genetic Laboratory, |
RCV001283811 | SCV001469208 | likely pathogenic | Short-rib thoracic dysplasia 14 with polydactyly | 2020-09-10 | no assertion criteria provided | clinical testing | |
Diagnostic Laboratory, |
RCV000255927 | SCV001741665 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Gene |
RCV000186590 | SCV001792274 | not provided | Joubert syndrome 23 | no assertion provided | literature only | ||
Laboratory of Diagnostic Genome Analysis, |
RCV000255927 | SCV001800402 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV000255927 | SCV001929223 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000255927 | SCV001957601 | likely pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000255927 | SCV001964839 | pathogenic | not provided | no assertion criteria provided | clinical testing |