Submissions for variant NM_174878.3(CLRN1):c.502dup (p.Ile168fs)

dbSNP: rs746523071

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169229	SCV000220496	likely pathogenic	Usher syndrome type 3	2014-07-10	criteria provided, single submitter	literature only
Invitae	RCV001054127	SCV001218426	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile168Asnfs*5) in the CLRN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the CLRN1 protein. This variant is present in population databases (rs746523071, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 17893653). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188875). 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.
Blueprint Genetics	RCV001073703	SCV001239262	pathogenic	Retinal dystrophy	2017-04-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281991	SCV002572423	pathogenic	Usher syndrome	2022-08-29	criteria provided, single submitter	clinical testing	Variant summary: CLRN1 c.502dupA (p.Ile168AsnfsX5) 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 by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 250134 control chromosomes (gnomAD). c.502dupA has been reported in the literature to segregate with disease in multiple individuals from one family affected with Usher Syndrome (Ebermann_2007). These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002466459	SCV002761639	likely pathogenic	Retinitis pigmentosa 61	2022-01-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498841	SCV002808232	likely pathogenic	Retinitis pigmentosa; Retinitis pigmentosa 61; Usher syndrome type 3A	2021-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398866	SCV004105808	pathogenic	CLRN1-related condition	2022-10-24	criteria provided, single submitter	clinical testing	The CLRN1 c.541dupA variant is predicted to result in a frameshift and premature protein termination (p.Ile181Asnfs*5). This variant has been reported as pathogenic for Usher syndrome (described as c.502dupA; García-García et al. 2012. PubMed ID: 23304067; Ebermann et al 2007. PubMed ID: 17893653). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-150645919-A-AT). Frameshift variants in CLRN1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV002466459	SCV004214417	pathogenic	Retinitis pigmentosa 61	2023-05-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273481	SCV001456563	pathogenic	Usher syndrome type 3A	2020-09-16	no assertion criteria provided	clinical testing