ClinVar Miner

Submissions for variant NM_001329943.3(KIAA0586):c.1254-1G>C (rs757350052)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479178 SCV000569483 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing The c.1413-1G>C variant in the KIAA0586 gene has been reported previously, in trans with another KIAA0586 pathogenic variant, in association with Joubert syndrome (Roosing et al., 2015; Bachmann-Gagescu et al., 2015). This splice site variant destroys the canonical splice acceptor site in intron 11, and functional studies demonstrate that this variant leads to utilization of a cryptic splice acceptor site, resulting in an aberrant transcript and absent protein levels in patient fibroblasts (Roosing et al., 2015). The c.1413-1G>C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1413-1G>C as a pathogenic variant.
Invitae RCV000652577 SCV000774447 pathogenic Joubert syndrome 23; Short-rib thoracic dysplasia 14 with polydactyly 2018-07-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the KIAA0586 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs757350052, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with Joubert syndrome, and has also been observed to segregate with disease in several families (PMID: 26026149, 26096313, 26386044, 26437029, 28497568). These findings are consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.1209-1G>C, c.1254-1G>C, c.1413-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 204594). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547). Analysis of lymphocyte mRNA from affected individuals has shown that this variant causes aberrant splicing and a frameshifted transcript by utilization of a cryptic splice acceptor located 16 bp downstream, suggesting partial or complete loss-of-function of the KIAA0586 protein (PMID: 26026149). Loss-of-function variants in KIAA0586 are known to be pathogenic (PMID: 26096313, 26166481). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000186591 SCV000240167 pathogenic Joubert syndrome 23 2015-06-11 no assertion criteria provided literature only
UW Hindbrain Malformation Research Program,University of Washington RCV000186591 SCV000256432 pathogenic Joubert syndrome 23 2015-09-01 criteria provided, single submitter research

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