Submissions for variant NM_174878.3(CLRN1):c.189C>A (p.Tyr63Ter)

gnomAD frequency: 0.00001  dbSNP: rs111033267

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844690	SCV000065128	pathogenic	Rare genetic deafness	2012-12-24	criteria provided, single submitter	clinical testing	The Tyr63X variant in CLRN1 has been reported in a homozygous state in three sib lings with Usher syndrome from one family (Adato 2002, Aller 2004). This nonsens e variant leads to a premature termination codon at position 63, which is predic ted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Counsyl	RCV000004647	SCV000486175	pathogenic	Usher syndrome type 3	2016-04-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004647	SCV000919233	pathogenic	Usher syndrome type 3	2018-09-07	criteria provided, single submitter	clinical testing	Variant summary: CLRN1 c.189C>A (p.Tyr63X) 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. The variant allele was found at a frequency of 1.8e-05 in 277198 control chromosomes. c.189C>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Usher Syndrome Type 3 (Adato_2002; Garcia-Garcia_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376502	SCV001573675	pathogenic	Usher syndrome type 3A	2021-04-08	criteria provided, single submitter	research	The CLRN1 c.189C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384937	SCV001584632	pathogenic	not provided	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr63*) in the CLRN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLRN1 are known to be pathogenic (PMID: 11524702, 24498627). This variant is present in population databases (rs111033267, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 12080385, 23304067). ClinVar contains an entry for this variant (Variation ID: 4397). 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.
3billion	RCV001376502	SCV002058400	pathogenic	Usher syndrome type 3A	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004397, PMID:12080385). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000014, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003407275	SCV004114993	pathogenic	CLRN1-related disorder	2023-06-21	criteria provided, single submitter	clinical testing	The CLRN1 c.189C>A variant is predicted to result in premature protein termination (p.Tyr63*). This variant has been reported to be causative for autosomal recessive Usher syndrome or retinitis pigmentosa (Adato et al. 2002. PubMed ID: 12080385; Melo et al. 2014. PubMed ID: 24596593; Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-150690307-G-T). Nonsense variants in CLRN1 are expected to be pathogenic. Given the evidence, we interpret c.189C>A (p.Tyr63*) as pathogenic.
Baylor Genetics	RCV003466814	SCV004214406	pathogenic	Retinitis pigmentosa 61	2024-03-22	criteria provided, single submitter	clinical testing
OMIM	RCV000004647	SCV000024821	pathogenic	Usher syndrome type 3	2004-12-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505037	SCV000598874	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV000004647	SCV002081535	pathogenic	Usher syndrome type 3	2020-09-11	no assertion criteria provided	clinical testing