ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.1099G>A (p.Gly367Arg)

dbSNP: rs74315334
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Glaucoma Variant Curation Expert Panel RCV002247272 SCV002520352 pathogenic Glaucoma of childhood 2022-05-09 reviewed by expert panel curation The c.1099G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 367 (p.Gly367Arg). This variant was not found in any population of gnomAD (v2.1.1), meeting the <= 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.787, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712, 35196929) demonstrated that the Gly367Arg protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 35 segregations in 7 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17304254, 32300215, 12189160, 11815346), which fulfilled PP1_Strong (>=7 meioses in >1 family). 16 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 32300215, 12189160, 11774072, 9345106, 23453510, 12872267, 14627955, 12442283), which met PS4 (>= 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification >= 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting
GeneDx RCV000255116 SCV000321920 pathogenic not provided 2021-08-16 criteria provided, single submitter clinical testing Published functional studies demonstrate the variant results in failure to be secreted into the extracellular medium compared to wildtype (Gobeil et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25582056, 12872267, 9345106, 10974305, 16466712, 32300215, 11774072, 28282485, 29600168, 21655360, 26095806, 23129764, 10340787, 12189160, 11815346, 17304254, 25524706)
OMIM RCV000008415 SCV000028623 pathogenic Glaucoma 1, open angle, A 1997-11-01 no assertion criteria provided literature only

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