ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)

dbSNP: rs74315338
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Glaucoma Variant Curation Expert Panel RCV002247274 SCV002520337 pathogenic Glaucoma of childhood 2022-05-09 reviewed by expert panel curation The c.1297T>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 433 (p.Cys433Arg). 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 = 0.913, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Cys433Arg protein had 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. 23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (>= 15 probands). 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.
OMIM RCV000008419 SCV000028627 pathogenic Glaucoma 1, open angle, A 2000-04-01 no assertion criteria provided literature only

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