rs534542684

chr14-58432438-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001329943.3(KIAA0586):c.392del(p.Arg131LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00383 in 1,568,644 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (14 hom.)
• Consequence: KIAA0586 NM_001329943.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35 O:1
• Conservation: PhyloP100: 4.54

Genes affected

KIAA0586 (HGNC:19960): (KIAA0586) This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-58432438-AG-A is Pathogenic according to our data. Variant chr14-58432438-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-58432438-AG-A is described in Lovd as [Likely_pathogenic]. Variant chr14-58432438-AG-A is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001329943.3	c.392del	p.Arg131LysfsTer4	frameshift_variant	4/31	ENST00000652326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000652326.2	c.392del	p.Arg131LysfsTer4	frameshift_variant	4/31		NM_001329943.3	P4

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 521 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00305 AC: 664 AN: 217674 Hom.: 1 AF XY: 0.00308 AC XY: 365 AN XY: 118584

Gnomad AFR exome AF: 0.000956

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00816

Gnomad EAS exome AF: 0.0000640

Gnomad SAS exome AF: 0.000417

Gnomad FIN exome AF: 0.000711

Gnomad NFE exome AF: 0.00462

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00388 AC: 5494 AN: 1416304 Hom.: 14 Cov.: 24 AF XY: 0.00386 AC XY: 2721 AN XY: 704672

Gnomad4 AFR exome AF: 0.000670

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.0000524

Gnomad4 SAS exome AF: 0.000584

Gnomad4 FIN exome AF: 0.000927

Gnomad4 NFE exome AF: 0.00440

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00342 AC: 521 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74514

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00498

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00372 Hom.: 1

Bravo AF: 0.00396

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 23 Pathogenic:12 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jan 13, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 21, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Sep 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 23, 2023	Identified as compund heterozygous with NM_001329943.3:c.3142_3144+5del. Criteria applied: PVS1,PM3_VSTR -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 12, 2024	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). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 23, 2022	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 03, 2020	ACMG codes:PVS1, PM3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 02, 2017	- -

not provided Pathogenic:12

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KIAA0586: PVS1, PM3, PM2:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 13, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 18, 2021	PVS1, PM3_strong -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 23, 2021	- -

Familial aplasia of the vermis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 07, 2016	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. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -

Short-rib thoracic dysplasia 14 with polydactyly Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Sep 10, 2020

- -

Joubert syndrome and related disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 23, 2021

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. -

KIAA0586-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

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. Based on above information, this variant is interpreted as pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 07, 2018

- -

Intellectual disability;C4551714:Rod-cone dystrophy;C5231391:Congenital cerebellar hypoplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs534542684; hg19: chr14-58899156;