Submissions for variant NM_000261.2(MYOC):c.568G>T (p.Asp190Tyr)

gnomAD frequency: 0.00005  dbSNP: rs201930435

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV003147444	SCV003836508	uncertain significance	Open-angle glaucoma	2023-02-15	reviewed by expert panel	curation	The c.568G>T variant in MYOC is a missense variant predicted to cause substitution of Aspartate by Tyrosine at amino acid 190 (p.Asp190Tyr). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.0001847 (21 alleles out of 113,682), which did not meet the PM2_Supporting allele frequency threshold (<=0.0001) or the BS1 allele frequency threshold (>=0.001). The REVEL score = 0.113, which met the <=0.15 threshold for BP4, suggesting that the variant does not impact 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 met the criteria to receive a score of -1 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): BP4.
Illumina Laboratory Services, Illumina	RCV000295103	SCV000351295	uncertain significance	Glaucoma	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000352302	SCV000351296	uncertain significance	Glaucoma 1, open angle, A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002519409	SCV003691473	uncertain significance	Inborn genetic diseases	2022-04-28	criteria provided, single submitter	clinical testing	The c.568G>T (p.D190Y) alteration is located in exon 1 (coding exon 1) of the MYOC gene. This alteration results from a G to T substitution at nucleotide position 568, causing the aspartic acid (D) at amino acid position 190 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003105856	SCV003782613	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 293716). This variant has not been reported in the literature in individuals affected with MYOC-related conditions. This variant is present in population databases (rs201930435, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 190 of the MYOC protein (p.Asp190Tyr).