ClinVar Miner

Submissions for variant NM_174878.3(CLRN1):c.118T>G (p.Cys40Gly)

gnomAD frequency: 0.00004  dbSNP: rs121908143
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000414238 SCV000337866 uncertain significance not provided 2015-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000414238 SCV000490476 likely pathogenic not provided 2022-12-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25743179, 23304067, 21310491, 15521980, 19753315, 29545425, 31963381, 29331482)
Counsyl RCV000004649 SCV000800518 uncertain significance Usher syndrome type 3 2017-04-19 criteria provided, single submitter clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals RCV000004649 SCV001156372 pathogenic Usher syndrome type 3 2019-02-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075346 SCV001240966 uncertain significance Retinal dystrophy 2018-04-11 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000414238 SCV001905531 likely pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
Invitae RCV000414238 SCV002163401 pathogenic not provided 2022-10-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 40 of the CLRN1 protein (p.Cys40Gly). This variant is present in population databases (rs121908143, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 15521980; Invitae). ClinVar contains an entry for this variant (Variation ID: 4399). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002468960 SCV002766549 likely pathogenic Usher syndrome 2022-11-14 criteria provided, single submitter clinical testing Variant summary: CLRN1 c.118T>G (p.Cys40Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251462 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CLRN1 causing Usher Syndrome (8e-05 vs 0.0014), allowing no conclusion about variant significance. c.118T>G has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in individuals affected with features of Usher Syndrome type 3 and as a heterozygous genotype in one case report with Unilateral retinitis pigmentosa (RP) (example, Aller_2004, Haer-Wigman_2017, Yong Sim_2018, Whelan_2020, Jiman_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP/P, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV003466815 SCV004214403 likely pathogenic Retinitis pigmentosa 61 2023-10-14 criteria provided, single submitter clinical testing
OMIM RCV000004649 SCV000024823 pathogenic Usher syndrome type 3 2004-12-01 no assertion criteria provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000004649 SCV000804616 uncertain significance Usher syndrome type 3 2016-09-01 no assertion criteria provided clinical testing
Natera, Inc. RCV001273484 SCV001456566 likely pathogenic Usher syndrome type 3A 2020-09-16 no assertion criteria provided clinical testing

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