ClinVar Miner

Submissions for variant NM_023073.3(CPLANE1):c.424G>A (p.Glu142Lys) (rs756856188)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201674 SCV000256327 pathogenic Joubert syndrome 17 2015-02-23 criteria provided, single submitter research
Genetic Services Laboratory, University of Chicago RCV000500106 SCV000593810 uncertain significance not specified 2016-09-23 criteria provided, single submitter clinical testing
Invitae RCV000686452 SCV000813971 pathogenic not provided 2020-09-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 142 of the CPLANE1 protein (p.Glu142Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs756856188, ExAC 0.05%). This variant has been observed in combination with another CPLANE1 variant in several individuals affected with Joubert syndrome (PMID: 26092869). This variant is also known as C5ORF42 p.Glu142Lys in the literature. ClinVar contains an entry for this variant (Variation ID: 217592). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000201674 SCV001441548 likely pathogenic Joubert syndrome 17 2020-10-27 criteria provided, single submitter clinical testing This CPLANE1 variant (rs756856188) is rare (<0.1%) in a large population dataset (26/188926 total alleles; 0.014%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a compound heterozygous state in multiple unrelated individuals affected with JS. Three bioinformatics tools predict this variant would be damaging, and the glutamate residue at this position is strongly conserved across all species assessed. This variant is not predicted to affect normal exon 5 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.424G>A to be likely pathogenic.
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328280 SCV001449201 uncertain significance Nephronophthisis 2018-05-31 no assertion criteria provided clinical testing This patient is also heterozygous for a variant of unknown clinical significance (VOUS), c.424G>A (p.Glu142Lys), in the C5orf42 gene. This variant (dbSNP: rs756856188) has been previously reported in the ExAC database (http://exac.broadinstitute.org/) with a very low allele frequency of 0.009% (2/22076 alleles). c.424G>A (p.Glu142Lys) has also been reported as a compound heterozygous variant in a patient with Joubert syndrome (Bachmann-Gagescu et al. J.Med.Genet 2015; 52:514-522). In silico analysis (Alamut Visual v2.8) using PolyPhen2, SIFT and Mutation Taster all predict that this variant is likely to be pathogenic.

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