Submissions for variant NM_001384732.1(CPLANE1):c.9220C>T (p.Arg3074Ter)

gnomAD frequency: 0.00019  dbSNP: rs374144275

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201669	SCV000256301	pathogenic	Joubert syndrome 17	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000357854	SCV000330558	pathogenic	not provided	2021-10-27	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26092869)
Invitae	RCV000357854	SCV001590557	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg3020*) in the CPLANE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPLANE1 are known to be pathogenic (PMID: 24178751, 26092869). This variant is present in population databases (rs374144275, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217569). 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.
DASA	RCV001849341	SCV002107125	pathogenic	Familial aplasia of the vermis	2022-03-05	criteria provided, single submitter	clinical testing	The c.9058C>T;p.(Arg3020*) variant creates a premature translational stop signal in the CPLANE1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217569; PMID: 26092869) - PS4_moderate. The variant is present at low allele frequencies population databases (rs374144275 – gnomAD 0.0004228%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg3020*) was detected in trans with a pathogenic variant (PMID: 26092869) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252055	SCV002523878	pathogenic	See cases	2020-11-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PS4, PM2, PM3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298520	SCV002598946	likely pathogenic	Joubert syndrome and related disorders	2022-09-25	criteria provided, single submitter	clinical testing	Variant summary: CPLANE1 c.9058C>T (p.Arg3020X), also known as c.9220C>T (p.Arg3074X), results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.9376C>T [p.Gln3126Ter]; c.9339dup [p.Ala3114fs]). The variant allele was found at a frequency of 4.2e-05 in 260162 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders (4.2e-05 vs 0.0015), allowing no conclusion about variant significance. c.9058C>T has been reported in the literature as a biallelic genotype in at least one individual affected with Joubert Syndrome And Related Disorders (Bachmann-Gagescu_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: all six classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000697060	SCV002796386	pathogenic	Orofaciodigital syndrome type 6; Joubert syndrome 17	2022-02-10	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000357854	SCV001741890	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000357854	SCV001963787	pathogenic	not provided		no assertion criteria provided	clinical testing