ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.1276G>T (p.Val426Phe)

dbSNP: rs2102944566
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Glaucoma Variant Curation Expert Panel RCV002248287 SCV002520335 likely pathogenic Glaucoma of childhood 2022-05-09 reviewed by expert panel curation The c.1276G>T variant in MYOC is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 426 (p.Val426Phe). 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 = 0.764, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Val426Phe 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. 26 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9521427, 9772276, 12671462), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23922489, 9521427, 9772276, 12671462), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) 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, PP3, PS4_Supporting, PM2_Supporting.

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