ClinVar Miner

Submissions for variant NM_023073.3(CPLANE1):c.3577C>T (p.Arg1193Cys) (rs149170427)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255984 SCV000321491 likely pathogenic not provided 2016-07-13 criteria provided, single submitter clinical testing The R1193C variant in the C5orf42 gene has been reported previously in the presence of another C5orf42 variants in unrelated individuals with clinical diagnoses of OFD IV and Joubert syndrome (Lopez et al., 2014; Ohba et al., 2013). The R1193C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1193C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R1193C as a likely pathogenic variant.
Invitae RCV000646706 SCV000768485 pathogenic Orofaciodigital syndrome type 6; Joubert syndrome 17 2017-08-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1193 of the C5orf42 protein (p.Arg1193Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs149170427, ExAC 0.01%). This variant has been reported as homozygous or in combination with another C5orf42 variant in individuals affected with Joubert syndrome (PMID: 24091540, 24178751, 27434533, 28431631). ClinVar contains an entry for this variant (Variation ID: 265062). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV001004928 SCV001164445 likely pathogenic Joubert syndrome 17 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg1193Cys variant in C5orf42 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with Joubert syndrome. This variant has been identified in 0.005798% (1/17248) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149170427). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools do not provide strong support for or against an impact to the protein. The p.Arg1193Cys variant in C5orf42 has been reported in 6 unrelated Japanese individuals with Joubert syndrome, including 2 individuals with the variant in the homozygous state and 4 individuals with the variant in the compound heterozygous state (PMID: 24091540, 24178751, 27434533, 28431631). The presence of this variant in combination with 4 unique variants (1 reported by our study, 1 reported pathogenic in ClinVar, 2 reported in the literature) and in an individual with Joubert syndrome increases the likelihood that the p.Arg1193Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1193Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_Strong (Richards 2015).

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