Submissions for variant NM_001329943.3(KIAA0586):c.94dup (p.His32fs)

gnomAD frequency: 0.00053  dbSNP: rs555421894

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513804	SCV000609943	likely pathogenic	not provided	2017-03-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000513804	SCV000702601	likely pathogenic	not provided	2016-11-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705869	SCV000834886	pathogenic	Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His44Profs*8) 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 (rs555421894, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with features of both Joubert syndrome and Jeune asphyxiating thoracic dystrophy and Joubert syndrome (PMID: 26096313, 26386044). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 445497). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
New York Genome Center	RCV001291733	SCV001480321	likely pathogenic	Joubert syndrome 23	2019-09-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000513804	SCV002000786	pathogenic	not provided	2022-05-27	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: 26096313, 28497568, 26386044, 27535533)
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001778987	SCV002016272	pathogenic	Neurodevelopmental disorder	2021-06-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000513804	SCV002023239	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003403203	SCV004104254	pathogenic	KIAA0586-related disorder	2023-01-25	criteria provided, single submitter	clinical testing	The KIAA0586 c.130dupC variant is predicted to result in a frameshift and premature protein termination (p.His44Profs*8). This variant (also known as c.94dup in an alternate transcript) has been reported to be causative for autosomal recessive Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26096313; Table S2 - Summers et al. 2017. PubMed ID: 28497568). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-58895075-T-TC). Frameshift variants in KIAA0586 are expected to be pathogenic and this variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/445497). This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003403202	SCV004122741	pathogenic	Joubert syndrome and related disorders	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: KIAA0586 c.130dupC (p.His44ProfsX8) 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 0.00028 in 249262 control chromosomes. c.130dupC has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders, including at least one individual with a compound heterozygous genotype (e.g. Summers_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28497568). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=4), likely pathogenic (n=3), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV001074911	SCV001240516	uncertain significance	Retinal dystrophy	2017-03-03	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV000705869	SCV002075216	not provided	Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 07-21-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.