Submissions for variant NM_000261.2(MYOC):c.1348A>T (p.Asn450Tyr)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV003233472	SCV003932335	likely pathogenic	Glaucoma of childhood	2023-05-31	reviewed by expert panel	curation	The c.1348A>T variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Tyrosine at amino acid 450 (p.Asn450Tyr). 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 = 0.68, 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 transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825), meeting PS3. 9 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 20806035), which fulfilled PP1_Moderate (>=5 meioses in >=1 family, but not the >=7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 20806035), not meeting the >= 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 7 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): PS3, PP1_Moderate, PM2_Supporting