Submissions for variant NM_000261.2(MYOC):c.136C>T (p.Arg46Ter)

gnomAD frequency: 0.00024  dbSNP: rs74315337

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV001824115	SCV002073861	likely benign	Glaucoma of childhood	2022-02-07	reviewed by expert panel	curation	The c.136C>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Arginine at amino acid 46. Truncation of this protein occurs outside of the conserved olfactomedin domain, which did not meet PM4. The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.009224, which met the >= 0.001 threshold set for BS1 (184 alleles out of 19 948, meeting the threshold of >= 5 of at least 2,000 observed alleles). There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma 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 -4 and to be classified as likely benign (likely benign classification range -2 to -6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000944958	SCV001090941	benign	not provided	2023-08-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001100518	SCV001257042	likely benign	Glaucoma	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000991157	SCV001257043	likely benign	Glaucoma 1, open angle, A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Fulgent Genetics, Fulgent Genetics	RCV000991157	SCV002808317	likely benign	Glaucoma 1, open angle, A	2022-05-16	criteria provided, single submitter	clinical testing
OMIM	RCV004577710	SCV000028626	pathogenic	RECLASSIFIED - POLYMORPHISM	1999-06-01	flagged submission	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000991157	SCV001142313	pathogenic	Glaucoma 1, open angle, A	2020-01-06	flagged submission	curation	NM_000261.1:c.136C>T in the MYOC gene has an allele frequency of 0.009 in East Asian subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.136C>T (Arg46Stop) mutation has been detected in three Taiwanese patients suffering from juvenile-onset open-angle glaucoma and one Korean patient with primary open-Angle glaucoma (PMID: 17893664; 10330365). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP4.