Submissions for variant NM_000261.2(MYOC):c.648G>A (p.Lys216=)

gnomAD frequency: 0.00053  dbSNP: rs141584495

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV001824149	SCV002073864	uncertain significance	Glaucoma 1, open angle, E	2022-02-07	reviewed by expert panel	curation	The c.648G>A variant in MYOC is a synonymous variant (p.Lys216=). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0009472 (29 alleles out of 30 616), which did not meet the PM2_Supporting allele frequency threshold (<= 0.0001) or the BS1 allele frequency threshold (>= 0.001). Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (<= 0.2), it had a CADD score (v1.6) = 11.58, which does not meet the <= 10 threshold for BP4 and a GERP score = 4.38 (threshold <0), not meeting BP7 and indicating conservation at this site. Although probands with primary open angle glaucoma have 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	RCV000334709	SCV000351293	uncertain significance	Glaucoma 1, open angle, A	2018-01-12	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	RCV000402548	SCV000351294	uncertain significance	Glaucoma	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001523294	SCV001732974	benign	not provided	2023-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001523294	SCV001998344	uncertain significance	not provided	2021-04-28	criteria provided, single submitter	clinical testing	Identified in patients with primary open-angel glaucoma in published literature (O'Gorman et al., 2019); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30816137)
Ambry Genetics	RCV004021374	SCV004953433	likely benign	Inborn genetic diseases	2023-09-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.