ClinVar Genomic variation as it relates to human health

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.

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).

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.

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.

ACMG codes:PVS1, PM3, PP5

PVS1, PM3_strong

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)

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.

KIAA0586: PVS1, PM3, PM2:Supporting

Identified as compund heterozygous with NM_001329943.3:c.3142_3144+5del. Criteria applied: PVS1,PM3_VSTR

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).

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

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

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.

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.

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.