Submissions for variant NM_000261.2(MYOC):c.1100_1103delinsT (p.Gly367_Gln368delinsVal)

dbSNP: rs2102944655

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV001843413	SCV002102547	likely pathogenic	Glaucoma of childhood	2022-03-05	reviewed by expert panel	curation	The c.1100_1103delinsT variant is predicted to cause a change in the length of the myocilin protein due to an in-frame deletion of Gly367 and Gln368 with an insertion of Valine (p.Gly367_Gln368delinsVal). This variant is predicted to cause a deletion of < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. 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. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. A previous study (PMID: 10545602) demonstrated that the Gly367_Gln368delinsVal protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 20 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9639450), which fulfilled PP1_Strong (>=7 meioses in >1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9639450), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 8 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_Supporting, PS4_Supporting, PM2_Supporting, PM4_Supporting