ClinVar Miner

Submissions for variant NM_001195794.1(CLRN1):c.149_152delinsTGTCCAAT (p.Ser50fs) (rs786204428)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169027 SCV000220175 likely pathogenic Usher syndrome, type 3A 2014-03-17 criteria provided, single submitter literature only
Genetic Services Laboratory, University of Chicago RCV000169027 SCV000247047 pathogenic Usher syndrome, type 3A 2015-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000478734 SCV000566125 pathogenic not provided 2016-05-13 criteria provided, single submitter clinical testing The c.149_152delCAGGinsTGTCCAAT pathogenic variant in the CLRN1 gene has been reportedpreviously in association with Usher syndrome type III (Fields et al., 2002; Le Quesne Stabej et al.,2012). The second study is a comprehensive clinical and genetic analysis of 172 Usher patientsincluding 2 families with Usher syndrome type III. In one of these families, segregation analysisconfirmed the c.149_152delCAGGinsTGTCCAAT pathogenic variant in a homozygous state (LeQuesne Stabej et al., 2012). The deletion and insertion causes a frameshift starting with codon Serine50, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 12 ofthe new reading frame, denoted p.Ser50LeufsX12. This pathogenic variant is predicted to cause lossof normal protein function either through protein truncation or nonsense-mediated mRNA decay. Thec.149_152delCAGGinsTGTCCAAT variant was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. Therefore, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169027 SCV000699979 pathogenic Usher syndrome, type 3A 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, Partners HealthCare 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,; 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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

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