Submissions for variant NM_001384732.1(CPLANE1):c.3828T>C (p.Leu1276=)

gnomAD frequency: 0.00087  dbSNP: rs145520487

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724250	SCV000227961	uncertain significance	not provided	2014-12-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000254359	SCV000314186	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000201620	SCV000457403	uncertain significance	Joubert syndrome 17	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000724250	SCV000978009	likely benign	not provided	2020-09-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26092869)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724250	SCV001021395	benign	not provided	2025-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724250	SCV004160918	likely benign	not provided	2025-01-01	criteria provided, single submitter	clinical testing	CPLANE1: BP4, BP7
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254359	SCV004242069	benign	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: CPLANE1 c.3828T>C alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00092 in 1613030 control chromosomes, predominantly at a frequency of 0.002 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders phenotype (0.0015), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3828T>C has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders (Bachman_2015). 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. The following publication have been ascertained in the context of this evaluation (PMID: 26092869). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=3), likely pathogenic (n=1) and pathogenic (n=1). Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV004020091	SCV004850601	likely benign	Inborn genetic diseases	2022-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
UW Hindbrain Malformation Research Program, University of Washington	RCV000201620	SCV000256329	likely pathogenic	Joubert syndrome 17	2015-02-23	flagged submission	research