Submissions for variant NM_174878.3(CLRN1):c.433+1G>A

gnomAD frequency: 0.00001  dbSNP: rs201205811

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
The Cell Therapy Center, The University of Jordan	RCV000791320	SCV000920580	pathogenic	Usher syndrome type 3	2019-03-15	criteria provided, single submitter	research	The c.433+1G>A variant in CLRN1 was found in a Jordanian family with inherited retinal dystrophy. This family was diagnosed with RP until after the molecular assessment showed CLRN1 as the causative gene. Audiometry revealed that all patients have some degree of sensorineural hearing loss which led to the diagnosis of Usher Syndrome. The variant was found in the proband and segregates with the disease. Simulation analysis including molecular and dynamic simulation was done on this variant and showed that it affected splicing tremendously resulting in an abnormal protein. In summary, the variant meets the criteria to be pathogenic based on its segregation, allele frequency, and simulation results.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387204	SCV001587768	pathogenic	not provided	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the CLRN1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs201205811, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CLRN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 638640). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the CLRN1 protein in which other variant(s) (p.Arg207*) have been determined to be pathogenic (PMID: 22952768, 23304067, 26338283). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003467324	SCV004214407	pathogenic	Retinitis pigmentosa 61	2023-12-26	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000791320	SCV001160989	pathogenic	Usher syndrome type 3	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV000791320	SCV002081531	pathogenic	Usher syndrome type 3	2020-09-23	no assertion criteria provided	clinical testing