ClinVar Miner

Submissions for variant NM_174878.3(CLRN1):c.368C>A (p.Ala123Asp)

gnomAD frequency: 0.00018  dbSNP: rs374963432
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000844624 SCV000065131 pathogenic Rare genetic deafness 2011-05-17 criteria provided, single submitter clinical testing The Ala123Asp variant has been reported in two individuals with Usher syndrome a nd was absent from 566 control chromosomes (Ebermann 2007, Isosomppi 2009). In a ddition, functional studies showed that the variant protein is not correctly loc alized in the cell and is rapidly degraded (Isosomppi 2009). In summary, this da ta meets our criteria to classify this variant as pathogenic.
Counsyl RCV000041436 SCV000220455 likely pathogenic Usher syndrome type 3 2014-06-27 criteria provided, single submitter literature only
Baylor Genetics RCV000041436 SCV001162963 likely pathogenic Usher syndrome type 3 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001071445 SCV001236751 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 123 of the CLRN1 protein (p.Ala123Asp). This variant is present in population databases (rs374963432, gnomAD 0.04%). This missense change has been observed in individuals with Usher syndrome (PMID: 7407589, 19753315, 27460420). ClinVar contains an entry for this variant (Variation ID: 48146). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLRN1 function (PMID: 19753315). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001582535 SCV001821386 pathogenic Usher syndrome 2021-08-24 criteria provided, single submitter clinical testing Variant summary: CLRN1 c.368C>A (p.Ala123Asp) results in a non-conservative amino acid change located in the transmembrane domain (Yoshimura_2015) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-05 in 283350 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in CLRN1 causing Usher Syndrome (3.9e-05 vs 0.0014), allowing no conclusion about variant significance. c.368C>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including two homozygotes (Ebermann_2007, Isosomppi_2009, Bonnet_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant results in CLRN1 protein retained in the ER and not trafficked to the plasma membrane (Isosomppi_2009). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002243688 SCV002512705 likely pathogenic Usher syndrome type 3A 2022-01-04 criteria provided, single submitter clinical testing ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM3 supporting, PP3 supporting
Baylor Genetics RCV003466890 SCV004214402 likely pathogenic Retinitis pigmentosa 61 2024-02-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000041436 SCV002081534 pathogenic Usher syndrome type 3 2021-01-13 no assertion criteria provided clinical testing

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