Submissions for variant NM_001384732.1(CPLANE1):c.8462-1G>C

gnomAD frequency: 0.00060  dbSNP: rs151279194

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178539	SCV000230636	likely pathogenic	not provided	2016-08-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000178539	SCV000524825	likely pathogenic	not provided	2024-04-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Identified in an individual with diabetic kidney disease (Lazaro-Guevara et al., 2020); This variant is associated with the following publications: (PMID: 31980526, 25533962)
Illumina Laboratory Services, Illumina	RCV000778764	SCV000915131	uncertain significance	Joubert syndrome 17	2018-10-09	criteria provided, single submitter	clinical testing	The C5orf42 c.8300-1G>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The variant is reported at a frequency of 0.000729 in the European (non-Finnish) population from the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for Joubert syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV000178539	SCV001247550	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	CPLANE1: PVS1:Strong, PM2
Baylor Genetics	RCV000778764	SCV001524831	uncertain significance	Joubert syndrome 17	2024-02-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824663	SCV002074350	uncertain significance	not specified	2024-01-16	criteria provided, single submitter	clinical testing	Variant summary: CPLANE1 c.8300-1G>C alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. One computational tool predicts an impact on normal splicing by abolishing a canonical 3' splice acceptor site. Three predict a non-informative impact on splicing based on lack of predictions for the wild-type and mutant sequences. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00076 in 1574996 control chromosomes in the gnomAD v4.0.0 database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders (0.00076 vs 0.0015), allowing no conclusion about variant significance. c.8300-1G>C has been reported in the literature as a heterozygous genotype with a likely pathogenic outcome in at-least one adult individual analyzed as part of a 3-year precision medicine study (example, Claire_2020). The exact clinical outcome, family history or the genotype of this occurrence is not clearly specified and the basis out the reported classification seems to be driven by the perceived translational outcome not bolstered by other supporting evidence as reported. Additionally, the variant has been reported in an individual with diabetic kidney disease (e.g., Lazaro-Guevara_2021). These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 31980526, 33774617). ClinVar contains an entry for this variant (Variation ID: 197492). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV002287379	SCV002577956	pathogenic	See cases	2022-01-31	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PP3,PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV000178539	SCV003011128	likely pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 42 of the CPLANE1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CPLANE1 are known to be pathogenic (PMID: 24178751, 26092869). This variant is present in population databases (rs151279194, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with CPLANE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 197492). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV003457649	SCV004177249	uncertain significance	Orofaciodigital syndrome type 6		criteria provided, single submitter	not provided
Ambry Genetics	RCV004020124	SCV004850631	uncertain significance	Inborn genetic diseases	2021-12-16	criteria provided, single submitter	clinical testing	Resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000778764	SCV005399811	uncertain significance	Joubert syndrome 17	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 17 (MIM#614615) and orofaciodigital syndrome VI (MIM#277170). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (101 heterozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0705 - No comparable splice acceptor variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. Reported as VUS, pathogenic and likely pathogenic (ClinVar, DECIPHER, LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005031712	SCV005672999	likely pathogenic	Orofaciodigital syndrome type 6; Joubert syndrome 17	2024-06-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752779	SCV005349335	uncertain significance	CPLANE1-related disorder	2024-08-29	no assertion criteria provided	clinical testing	The CPLANE1 c.8300-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in a genome sequencing cohort with unspecified disease association (Supplemental Table, Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.072% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including a homozygous individual in the latest dataset (https://gnomad.broadinstitute.org/variant/5-37142481-C-G?dataset=gnomad_r4). This variant has conflicted classifications in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/197492/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.