ClinVar

Description

The c.1255A>G variant in MYOC is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 419 (p.Thr419Ala). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.000008791 (1 allele out of 113,758), which met the <= 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.873, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 4 individuals with POAG have been reported carrying this variant (PMID: 30816137, Souzeau et al, 2021 and Albuainain et al, 2021). However, as they each also carry the pathogenic Gln368Ter variant (ClinVar ID:7949, classified pathogenic by the ClinGen Glaucoma VCEP), the role of Thr419Ala could not be established, thus probands were not included and PS4 was not met. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting