Submissions for variant NM_001384732.1(CPLANE1):c.4006C>T (p.Arg1336Trp)

gnomAD frequency: 0.00002  dbSNP: rs367543061

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000024218	SCV000256314	pathogenic	Joubert syndrome 17	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000522403	SCV000618376	likely pathogenic	not provided	2025-03-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31981491, 20301500, 26092869, 22425360, 26477546, 10488899, 25877302, 36789003, 31771860, 39125556)
CeGaT Center for Human Genetics Tuebingen	RCV000522403	SCV001501917	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271377	SCV002555886	pathogenic	Joubert syndrome and related disorders	2022-06-01	criteria provided, single submitter	clinical testing	Variant summary: CPLANE1 c.4006C>T (p.Arg1336Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 280178 control chromosomes. c.4006C>T has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Joubert Syndrome (example, Srour_2012, Bachmann-Gagescu_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories, a research program and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000522403	SCV003525783	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1336 of the CPLANE1 protein (p.Arg1336Trp). This variant is present in population databases (rs367543061, gnomAD 0.004%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 22425360). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CPLANE1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV003444055	SCV004171182	likely pathogenic	Joubert syndrome 1		criteria provided, single submitter	not provided
Fulgent Genetics, Fulgent Genetics	RCV005031455	SCV005672593	pathogenic	Orofaciodigital syndrome type 6; Joubert syndrome 17	2024-04-01	criteria provided, single submitter	clinical testing
OMIM	RCV000024218	SCV000045509	pathogenic	Joubert syndrome 17	2012-04-06	no assertion criteria provided	literature only
GeneReviews	RCV000024218	SCV000058550	not provided	Joubert syndrome 17		no assertion provided	literature only
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000024218	SCV004697953	likely pathogenic	Joubert syndrome 17		no assertion criteria provided	clinical testing