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: 42
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000652578 SCV000774448 pathogenic Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly 2025-02-02 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 2024-12-01 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 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
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000186590 SCV004800958 pathogenic Joubert syndrome 23 2024-03-12 criteria provided, single submitter curation The heterozygous p.Arg131LysfsTer4 variant in KIAA0586 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 423877), in one individual with abducens (cranial nerve VI) palsy, neonatal dysphagia, choroidal coloboma, developmental delay, cognitive impairment, scoliosis, pes planovalgus, and craniofacial dysmorphisms, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). This individual also carried a likely pathogenic variant (ClinVar Variation ID: 423877), however the phase of these variants is unknown at this time. We believe this is a possible phenotype expansion for autosomal recessive Joubert syndrome 23. The p.Arg131LysfsTer4 variant in KIAA0586 has been previously reported in at least 34 unrelated individuals with Joubert syndrome 23 (PMID: 26386247, PMID: 26026149, PMID: 26096313, PMID: 26386044, PMID: 30120217, PMID: 32381069, PMID: 28832562, PMID: 28497568, PMID: 26437029) and segregated with disease in 9 affected relatives from 4 families (PMID: 26437029, PMID: 30120217, PMID: 26026149), but has been identified in 0.06% (85/15286) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs534542684). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 34 affected individuals (PMID: 26386247, PMID: 26026149, PMID: 26096313, PMID: 26386044, PMID: 30120217, PMID: 32381069, PMID: 28832562, PMID: 28497568, PMID: 26437029), 31 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 28497568, ClinVar Variation ID: 204595; PMID: 28832562, ClinVar Variation ID: 369671; PMID: 32381069, ClinVar Variation ID: 583841, PMID: 30120217, ClinVar Variation ID: 204594, PMID: 26386247, ClinVar Variation ID: 418265; PMID: 26386044, ClinVar Variation ID: 583841, 204595, 204594; PMID: 26026149, ClinVar Variation ID: 1406363, 204594; PMID: 26437029, ClinVar Variation ID: 204594, 217669; PMID: 26096313, ClinVar Variation ID: 204594, 204595, 217668, 217669), which increases the likelihood that thep.Arg131LysfsTer4 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 204593) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 143 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the KIAA0586 gene is strongly associated to autosomal recessive Joubert syndrome 23. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Joubert syndrome 23. ACMG/AMP Criteria applied: PVS1_Strong, PM3_VeryStrong, PP1_Strong (Richards 2015).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000186590 SCV005085968 pathogenic Joubert syndrome 23 2024-09-20 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 23 (MIM#616490) and short-rib thoracic dysplasia 14 with polydactyly (MIM#616546). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 773 heterozygotes, 2 homozygotes; v3-nonv2: 405 heterozygotes, 1 homozygote). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been well reported as pathogenic, and as compound heterozygous in the majority of the affected individuals (ClinVar, DECIPHER, PMID: 36788019). Several affected homozygotes have been reported; however, several unaffected homozygotes have also been reported (gnomAD, PMIDs: 36788019, 30120217, 25807282). (SP) 1010 - Functional evidence for this variant is inconclusive. cDNA analysis from an unaffected mother who is homozygous for this variant showed the transcript containing this variant was expressed in her blood cells (PMID: 30120217). Functional studies using cells from an unaffected homozygote showed ciliation and ciliary length indistinguishable from healthy controls without this variant, whereas samples from a compound heterozygous affected individual and a homozygous affected individual showed a reduction of both the percentage of ciliated cells and ciliary length compared with controls (PMID: 36788019). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000255927 SCV005198575 pathogenic not provided 2022-07-13 criteria provided, single submitter clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV000186590 SCV005397376 pathogenic Joubert syndrome 23 2021-05-06 criteria provided, single submitter clinical testing This sequence variantis a single nucleotide deletion (delG) in exon 5 of 34, and may result in a truncated protein or loss of KIAA0586 expression due to nonsense mediated decay. This variant is present in control population datasets including 2 homozygotes (gnomAD database, 777/249074 alleles, or 0.3%), and has been observed in multiple individuals with Joubert syndrome and KIAA0586-related disorders (PMIDs: 26096313, 26386044). This variant is considered disease causing for a mild form of Joubert syndrome when identified in trans with a known pathogenic KIAA0586 variant (PMID: 26096313). It is important to note, that this variant has been detected in a homozygous state in uffected individuals in population databases and in the literature (PMID: 30120217). R alysis from an uffected homozygous individual suggests that KIAA0586 transcripts carrying this variant persist (PMID: 30120217); however, a separate study reports the absence of KIAA0586 protein product in individuals with compound heterozygous pathogenic variants (PMID: 26026149). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP5, PS3, PVS1
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV000186590 SCV005438410 pathogenic Joubert syndrome 23 2024-12-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV004984730 SCV005610671 pathogenic Inborn genetic diseases 2024-08-16 criteria provided, single submitter clinical testing The c.392delG (p.R131Kfs*4) alteration, located in exon 4 (coding exon 4) of the KIAA0586 gene, consists of a deletion of one nucleotide at position 392, causing a translational frameshift with a predicted alternate stop codon after 4 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.312% (777/249074) total alleles studied. The highest observed frequency was 0.834% (77/9238) of Ashkenazi Jewish alleles. This variant has been identified in conjunction with other KIAA0586 variants in individuals with features consistent with KIAA0586-related ciliopathies (Roosing, 2015; Sumathipala, 2020). In the homozygous state, this variant has been identified in individuals with KIAA0586-related ciliopathies including Joubert syndrome (Bachmann-Gagescu, 2015; Roosing, 2015; Serpieri, 2023), but has also demonstrated reduced penetrance (Sulem, 2015; Pauli, 2019). Based on the available evidence, this alteration is classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV005250030 SCV005900634 pathogenic KIAA0586- Related disorders 2024-10-08 criteria provided, single submitter clinical testing This variant is also referred to as c.392delG (p.Arg131LysfsTer4) in the literature based on transcript NM_001329943.3. This frameshifting variant in exon 5 of 34 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Loss-of-function variation in KIAA0586 is an established mechanism of disease (PMID: 20301500). This is a known Pathogenic variant that has been previously reported as a compound heterozygous or homozygous change in patients with Joubert syndrome (PMID: 26386247, 26026149, 26096313, 26386044, 30120217, 32381069, 28832562, 28497568, 26437029). Additionally, this variant has segregated with disease in multiple related individuals (PMID: 26026149, 26437029, 30120217). The c.428del (p.Arg143LysfsTer4) variant is a hypomorphic variant that may cause disease in the homozygous state if there is an additional hypomorphic variant in a different ciliopathy gene or it may cause disease in the compound heterozygous state when it is in trans with a more severe loss-of-function variant (PMID: 30120217). Functional studies of the c.428del (p.Arg143LysfsTer4) variant have had various results seemingly dependent on clinical affected status. A study demonstrated that cells from affected patients with this variant led to the loss of protein production (PMID: 26026149) and a reduction in the quantity of ciliated cells and ciliary length compared with wild-type (PMID: 36788019). However, other functional studies in cells from unaffected individuals who were homozygous for this variant did not show any differences in mRNA levels (PMID: 30120217) or the quantity of ciliated cells and ciliary length in comparison with wild-type (PMID: 36788019). The c.428del (p.Arg143LysfsTer4) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.4% (6015/1568644), including 16 homozygous individuals. Based on the available evidence, c.428del (p.Arg143LysfsTer4) is classified 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
PreventionGenetics, part of Exact Sciences RCV003401022 SCV004103141 pathogenic KIAA0586-related disorder 2024-09-17 no assertion criteria provided clinical testing The KIAA0586 c.428delG variant is predicted to result in a frameshift and premature protein termination (p.Arg143Lysfs*4). This variant has been 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. Based on this information, this variant is interpreted as pathogenic.

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