ClinVar Miner

Submissions for variant NM_001379500.1(COL18A1):c.3523_3524del (p.Leu1175fs)

gnomAD frequency: 0.00029  dbSNP: rs398122391
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479282 SCV000567322 pathogenic not provided 2022-01-04 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; This variant is associated with the following publications: (PMID: 21937992, 28041643, 25456301, 23667181, 19160445, 20979194, 31415705, 12415512, 33238767, 31896775, 32178553, 28950998, 32581362, 29977801)
Blueprint Genetics RCV001074487 SCV001240074 pathogenic Retinal dystrophy 2017-09-15 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198207 SCV001369077 pathogenic Glaucoma, primary closed-angle 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
Invitae RCV000479282 SCV001416967 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1172Valfs*72) in the COL18A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL18A1 are known to be pathogenic (PMID: 12415512, 25456301). This variant is present in population databases (rs398122391, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Knobloch syndrome (PMID: 19390655, 21862674, 23667181, 29977801). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu1587Valfs*72. ClinVar contains an entry for this variant (Variation ID: 65410). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000479282 SCV001447309 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000479282 SCV001501806 pathogenic not provided 2023-06-01 criteria provided, single submitter clinical testing COL18A1: PVS1, PM2, PM3
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000479282 SCV002051613 pathogenic not provided 2021-03-03 criteria provided, single submitter clinical testing PVS1, PM2, PM3
Genetic Services Laboratory, University of Chicago RCV000479282 SCV002064455 pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing
DASA RCV000055632 SCV002107162 pathogenic Knobloch syndrome 2022-03-05 criteria provided, single submitter clinical testing The c.4054_4055delCT;p.(Leu1355Valfs*72) is a null frameshift variant (NMD) in the COL18A1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65410; PMID: 29977801; PMID: 21862674; PMID: 23667181; PMID: 19390655) - PS4. The variant is present at low allele frequencies population databases (rs398122391 – gnomAD 0.002961%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002504954 SCV002812897 pathogenic Glaucoma, primary closed-angle; Knobloch syndrome 1 2022-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235024 SCV003934783 pathogenic Knobloch syndrome 1 2023-05-04 criteria provided, single submitter clinical testing Variant summary: COL18A1 c.3523_3524delCT (p.Leu1175ValfsX72) 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 0.0003 in 194886 control chromosomes. c.3523_3524delCT has been reported in the literature in individuals affected with Knobloch Syndrome 1 (example: Villanueva-Mendoza_2021). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34828430). 12 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 (n=11) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000055632 SCV000038936 pathogenic Knobloch syndrome 2010-11-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504900 SCV000598896 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505165 SCV000598897 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
Molecular Genetics Laboratory, Institute for Ophthalmic Research RCV000055632 SCV000924662 pathogenic Knobloch syndrome 2017-12-13 no assertion criteria provided research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000479282 SCV001952203 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000479282 SCV001973916 pathogenic not provided no assertion criteria provided clinical testing

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