ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.1309T>C (p.Tyr437His)

dbSNP: rs74315328
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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 RCV001843349 SCV002102555 pathogenic Glaucoma of childhood 2022-03-05 reviewed by expert panel curation The c.1309T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 437 (p.Tyr437His). 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 = 0.966, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Tyr437His 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. 39 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9535666, 30612094), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 6 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 10196380, 9792882, 30612094), which met PS4_Moderate (>= 6 probands). In summary, this variant met the criteria to receive a score of 10 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): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting.
OMIM RCV000008409 SCV000028617 pathogenic Glaucoma 1, open angle, A 1998-04-09 no assertion criteria provided literature only

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