ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.1440C>A (p.Asn480Lys)

dbSNP: rs74315332
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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 RCV002247271 SCV002520341 pathogenic Glaucoma of childhood 2022-05-09 reviewed by expert panel curation The c.1440C>A variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). 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 = 0.784, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys 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. Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), 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 RCV000008414 SCV000028622 pathogenic Glaucoma 1, open angle, A 1998-04-13 no assertion criteria provided literature only

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