Submissions for variant NM_001384732.1(CPLANE1):c.3577C>T (p.Arg1193Cys)

gnomAD frequency: 0.00002  dbSNP: rs149170427

Total submissions: 4

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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).
Invitae	RCV000255984	SCV001588174	pathogenic	not provided	2021-08-31	criteria provided, single submitter	clinical testing
Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	RCV004556055	SCV005045311	likely pathogenic	Orofaciodigital syndrome type 6	2024-02-01	no assertion criteria provided	clinical testing