Submissions for variant NM_001384732.1(CPLANE1):c.7588+7A>G

gnomAD frequency: 0.00001  dbSNP: rs773662834

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001361695	SCV001557678	pathogenic	not provided	2022-05-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 37 of the CPLANE1 gene. It does not directly change the encoded amino acid sequence of the CPLANE1 protein. This variant is present in population databases (rs773662834, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of Joubert syndrome and related disorders (PMID: 28431631; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 582245). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001361695	SCV002499930	uncertain significance	not provided	2022-03-30	criteria provided, single submitter	clinical testing	Identified with a second variant in a patient with Joubert syndrome in the published literature (Enokizono et al., 2017); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28431631)
Mendelics	RCV002249424	SCV002519433	pathogenic	Orofaciodigital syndrome type 6	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226375	SCV003923175	uncertain significance	not specified	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: CPLANE1 c.7588+7A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 2.4e-05 in 251190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. One computational tool (Trap) suggests that this variant could be possibly damaging. c.7588+7A>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Joubert Syndrome And Related Disorders (Enokizono_2017). This report does not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant as VUS (n=2) and Pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.