Submissions for variant NM_001195794.1(CLRN1):c.149_152delinsTGTCCAAT (p.Ser50fs)

dbSNP: rs786204428

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169027	SCV000220175	likely pathogenic	Usher syndrome type 3	2014-03-17	criteria provided, single submitter	literature only
Genetic Services Laboratory, University of Chicago	RCV000169027	SCV000247047	pathogenic	Usher syndrome type 3	2015-07-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000478734	SCV000566125	pathogenic	not provided	2022-11-17	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17893653, 18273898, 12145752, 22135276, 16963483)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169027	SCV000699979	pathogenic	Usher syndrome type 3	2017-01-19	criteria provided, single submitter	clinical testing	Variant summary: The CLRN1 c.149_152delinsTGTCCAAT (p.Ser50Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent CLRN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant is absent in 122580 control chromosomes while it was reported in several patients with Usher Syndrome in homozygosity or in compound heterozygosity with other pathogenic variant indicating pathogenicity. In addition, multiple clinical diagnostic laboratories classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844691	SCV000710848	pathogenic	Rare genetic deafness	2017-08-30	criteria provided, single submitter	clinical testing	The p.Ser50fs variant in CLRN1 has been reported in 3 individuals with Usher syn drome type III, who were either homozygous for the variant or compound heterozyg ous for this variant and a second pathogenic variant (Fields 2002 and Le Quesne Stabej 2012). The variant has also been reported in ClinVar by multiple submitte rs as a pathogenic variant (Variation ID: 188726). It has also been identified i n 0.02% (27/126690) of European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs786204428); however this freq uency is low enough to be consistent with a recessive carrier frequency. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CLRN1 gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome type III in an autos omal recessive manner.
Eurofins Ntd Llc (ga)	RCV000478734	SCV000856585	pathogenic	not provided	2017-08-24	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001073424	SCV001238965	pathogenic	Retinal dystrophy	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000478734	SCV001415472	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser50Leufs*12) 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 (rs762606406, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 12145752, 22135276). This variant is also known as c.149delCAGGinsTGTCCAAT. ClinVar contains an entry for this variant (Variation ID: 1275768). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485050	SCV002796698	pathogenic	Retinitis pigmentosa; Retinitis pigmentosa 61; Usher syndrome type 3A	2022-05-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468834	SCV004214411	pathogenic	Retinitis pigmentosa 61	2024-03-23	criteria provided, single submitter	clinical testing