ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.376C>T (p.Arg126Trp)

gnomAD frequency: 0.00014  dbSNP: rs200120115
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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 RCV001838826 SCV002098439 likely benign Glaucoma 1, open angle, E 2022-02-20 reviewed by expert panel curation The c.376C>T variant in MYOC is a missense variant predicted to cause substitution of Arginine by Tryptophan at amino acid 126 (p.Arg126Trp). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.0007057 (25 alleles out of 35,424), which did not meet the PM2_Supporting allele frequency threshold (<= 0.0001) or the BS1 allele frequency threshold (>= 0.001). The REVEL score = 0.561, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Arg126Trp protein had similar secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 2 segregations had been reported for primary open angle glaucoma, not meeting the >= 3 segregations required for PP1. Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate.
GeneDx RCV001756645 SCV001986188 uncertain significance not provided 2019-09-09 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14764620, 16466712, 30816137, 12189160)
Labcorp Genetics (formerly Invitae), Labcorp RCV001756645 SCV002325995 likely benign not provided 2022-06-20 criteria provided, single submitter clinical testing

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