Submissions for variant NM_001382391.1(CSPP1):c.2259_2260del (p.Glu755fs)

dbSNP: rs587777139

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000087067	SCV000256397	pathogenic	Joubert syndrome 21	2015-02-23	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000087067	SCV001367049	pathogenic	Joubert syndrome 21	2018-10-24	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000087067	SCV001415320	pathogenic	Joubert syndrome 21	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu750Glyfs*30) in the CSPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSPP1 are known to be pathogenic (PMID: 24360807, 24360808). This variant is present in population databases (rs751779946, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Joubert syndrome and Meckel syndrome (PMID: 24360807, 24360808, 27894351). ClinVar contains an entry for this variant (Variation ID: 100667). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000087067	SCV001525746	pathogenic	Joubert syndrome 21	2018-05-11	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. The c.2244_2245delAA (p.E750Gfs*30) variant has been previously reported as disease causing in individuals with Joubert syndrome [PMID 24360807, 27894351, 24360808]
GeneDx	RCV001555416	SCV001776834	pathogenic	not provided	2024-09-25	criteria provided, single submitter	clinical testing	Frameshift 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: 24360807, 24360808, 26092869, 27894351, 35183220, 31964843)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000087067	SCV002061742	pathogenic	Joubert syndrome 21	2021-12-22	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Fulgent Genetics, Fulgent Genetics	RCV000087067	SCV002798572	pathogenic	Joubert syndrome 21	2022-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000087067	SCV004029716	pathogenic	Joubert syndrome 21	2023-07-17	criteria provided, single submitter	clinical testing	Variant summary: CSPP1 c.2244_2245delAA (p.Glu750GlyfsX30) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 9.2e-05 in 238258 control chromosomes. c.2244_2245delAA has been reported in the literature in individuals affected with ciliopathies such as Joubert Syndrome and Meckel-Gruber-like syndrome ((example, Tuz_2014, Fleming_2017). The following publications have been ascertained in the context of this evaluation (PMID: 29146704, 24360808). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000087067	SCV000119881	pathogenic	Joubert syndrome 21	2014-01-02	no assertion criteria provided	literature only