VCV000007947.8 - ClinVar

NM_000261.2(MYOC):c.1091G>T (p.Gly364Val)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Open-angle glaucoma

Classification is based on the expert panel submission

Jan 2026 by ClinGen Glaucoma Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000261.2(MYOC):c.1091G>T (p.Gly364Val)

Variation ID: 7947 Accession: VCV000007947.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q24.3 1: 171636349 (GRCh38) [ NCBI UCSC ] 1: 171605489 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 9, 2018	Jan 24, 2026	Jan 20, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000261.2:c.1091G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000252.1:p.Gly364Val	missense
NC_000001.11:g.171636349C>A
NC_000001.10:g.171605489C>A
NG_008859.1:g.21285G>T
	Q99972:p.Gly364Val

... more HGVS ... less HGVS

Protein change

G364V

Other names

MYOC, GLY357VAL
NM_000261.2(MYOC):c.1091G>T

Canonical SPDI

NC_000001.11:171636348:C:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

UniProtKB: Q99972#VAR_005470 OMIM: 601652.0002 dbSNP: rs121909193 ClinGen: CA119170 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYOC		-	-	GRCh38 GRCh37	335	364

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glaucoma 1, open angle, A	Pathogenic (1)	no assertion criteria provided	Nov 7, 2018	RCV000008410.6
Open-angle glaucoma	Pathogenic (1)	reviewed by expert panel	Jan 20, 2026	RCV006449921.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 20, 2026) C Contributing to aggregate classification	reviewed by expert panel (ClinGen Glaucoma ACMG Specifications V2.0.0 Approved)	Open-angle glaucoma (Autosomal dominant inheritance)	ClinGen Glaucoma Variant Curation Expert Panel FDA Recognized Database Accession: SCV002098430.3 First in ClinVar: Feb 26, 2022 Last updated: Jan 24, 2026	Publications: PubMed (4) PubMed: 15069026‚ 21612213‚ 23129764‚ 25524706 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/30a3432f-835c-4e0b-942a-7a84d0c5f07c Comment: show The c.1091G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 364 (p.Gly364Val). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.896, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Gly364Val protein had increased instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. This protein has also been assessed in these other studies (PMIDs: 10545602, 11152659, 15069026, 16297911), however, the same level of evidence was not met. 18 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMID: 10196380), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP1_Strong, PS3_Moderate, PP3_Moderate, PS4_Supporting, PM2_Supporting. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Nov 07, 2018) N Not contributing to aggregate classification	no assertion criteria provided	GLAUCOMA 1, OPEN ANGLE, A	OMIM Accession: SCV000028618.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018	Publications: Stone, E. M. Personal (more...) Stone, E. M. Personal Communication. 1999. Iowa City, Iowa Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In 2 families, including a previously unreported adult-onset open angle glaucoma (137750) family with 15 affected members, Stone et al. (1997) detected a gly357-to-val mutation … (more) In 2 families, including a previously unreported adult-onset open angle glaucoma (137750) family with 15 affected members, Stone et al. (1997) detected a gly357-to-val mutation in the TIGR gene. (less)

Comment:

The c.1091G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 364 (p.Gly364Val). This variant was not found in any genetic ancestry group of gnomAD (v4.1.0), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.896, which was within the 0.773-0.931 range for PP3_Moderate, predicting a damaging effect on MYOC function. The Gly364Val protein had increased instability and reduced secretion levels compared to wild type myocilin protein in these studies (PMIDs: 16466712, 21612213, 23129764). The assays met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. This protein has also been assessed in these other studies (PMIDs: 10545602, 11152659, 15069026, 16297911), however, the same level of evidence was not met. 18 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMID: 10196380), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10, adapted from PMID: 32720330) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): PP1_Strong, PS3_Moderate, PP3_Moderate, PS4_Supporting, PM2_Supporting.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Structural basis for misfolding in myocilin-associated glaucoma.	Donegan RK	Human molecular genetics	2015	PMID: 25524706
The glaucoma-associated olfactomedin domain of myocilin is a novel calcium binding protein.	Donegan RK	The Journal of biological chemistry	2012	PMID: 23129764
The stability of myocilin olfactomedin domain variants provides new insight into glaucoma as a protein misfolding disorder.	Burns JN	Biochemistry	2011	PMID: 21612213
Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma.	Liu Y	Human molecular genetics	2004	PMID: 15069026
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/30a3432f-835c-4e0b-942a-7a84d0c5f07c	-	-	-	-
Stone, E. M. Personal Communication. 1999. Iowa City, Iowa	-	-	-	-

Text-mined citations for rs121909193 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 01, 2026