Submissions for variant NM_000261.2(MYOC):c.652G>A (p.Glu218Lys)

gnomAD frequency: 0.00001  dbSNP: rs200547613

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV003233950	SCV003932327	uncertain significance	Open-angle glaucoma	2023-05-31	reviewed by expert panel	curation	The c.652G>A variant in MYOC is a missense variant predicted to cause substitution of Glutamic Acid by Lysine at amino acid 218 (p.Glu218Lys). The highest allele frequency of this variant (in a population of at least 2,000 alleles) was in the "Other" population of gnomAD (v2.1.1) = 0.0001629 (1 allele out of 6,138) which did not meet the >= 0.001 threshold for BS1. The highest allele frequency of this variant (in a population of at least 10,000 alleles) was in the South Asian population of gnomAD (v2.1.1) = 0.0001307 (4 alleles out of 30,616), which did not meet the <= 0.0001 threshold set for PM2_Supporting. The REVEL score = 0.407, 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. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification 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): none
Illumina Laboratory Services, Illumina	RCV001098614	SCV001254996	uncertain significance	Glaucoma 1, open angle, A	2017-08-23	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001098615	SCV001254997	uncertain significance	Glaucoma	2017-08-23	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558664	SCV004281062	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 218 of the MYOC protein (p.Glu218Lys). This variant is present in population databases (rs200547613, gnomAD 0.01%). This missense change has been observed in individual(s) with glaucoma (PMID: 23922489). ClinVar contains an entry for this variant (Variation ID: 875084). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.