Submissions for variant NM_052995.2(CLRN1):c.300T>G (p.Tyr100Ter)

gnomAD frequency: 0.00089  dbSNP: rs121908140

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724158	SCV000700728	pathogenic	not provided	2016-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004642	SCV000919234	pathogenic	Usher syndrome type 3	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: CLRN1 c.528T>G (p.Tyr176X) 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 0.00073 in 277070 control chromosomes in the gnomAD database, including 2 homozygotes. The variant, c.528T>G, has been reported in the literature in multiple individuals affected with Usher Syndrome Type 3 and is considered the most common disease variant in Finland (Joensuu_2001, Isosomppi_2009). 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724158	SCV000935679	pathogenic	not provided	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr176*) in the CLRN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the CLRN1 protein. This variant is present in population databases (rs121908140, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Usher syndrome type 3 (PMID: 11524702, 12145752, 22681893). 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. This variant is also known as Y100X. ClinVar contains an entry for this variant (Variation ID: 4392). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CLRN1 function (PMID: 19753315). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000724158	SCV001447860	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375084	SCV001571901	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Moderate,
GeneDx	RCV000724158	SCV001813545	pathogenic	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 57 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD.; This variant is associated with the following publications: (PMID: 29068140, 27460420, 29490346, 11524702, 25525159, 31456290, 35481838)
Mendelics	RCV002247246	SCV002518724	pathogenic	Retinitis pigmentosa	2022-05-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496258	SCV002807868	pathogenic	Retinitis pigmentosa; Retinitis pigmentosa 61; Usher syndrome type 3A	2022-01-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466811	SCV004214399	pathogenic	Retinitis pigmentosa 61	2024-03-11	criteria provided, single submitter	clinical testing
OMIM	RCV000004642	SCV000024816	pathogenic	Usher syndrome type 3	2002-09-01	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000004642	SCV000804617	pathogenic	Usher syndrome type 3	2016-09-01	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000004642	SCV001142331	pathogenic	Usher syndrome type 3	2020-01-06	no assertion criteria provided	curation	NM_174878.2:c.528T>G in the CLRN1 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. This nonsense c.528T>G (p.Tyr176*) variant has been previously identified in 52 homozygous and 2 compound heterozygous individuals with Usher syndrome type III (PMID: 11524702). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP4.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000004642	SCV001160987	pathogenic	Usher syndrome type 3	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV000004642	SCV002081528	pathogenic	Usher syndrome type 3	2020-05-30	no assertion criteria provided	clinical testing