Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000261.2:c.608C>T

CA343727142

1342208 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: 27008272-946b-44b3-8a05-45be2c558549

Approved on: 2025-12-04

Published on: 2025-12-04

HGVS expressions

NM_000261.2:c.608C>T

NC_000001.11:g.171638719G>A

CM000663.2:g.171638719G>A

NC_000001.10:g.171607859G>A

CM000663.1:g.171607859G>A

NC_000001.9:g.169874482G>A

NG_008859.1:g.18915C>T

ENST00000037502.11:c.608C>T

ENST00000637303.1:c.324G>A

ENST00000638471.1:c.138C>T

ENST00000037502.10:c.608C>T

ENST00000614688.1:c.608C>T

NM_000261.1:c.608C>T

Uncertain Significance

PM2_Supporting BS3_Supporting

PM5 PM4 BA1 BS1 BP4 BP7 PS4 PS2 PS1 PS3 PP1 PP3

Evidence Links 1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYOC Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.608C>T variant in MYOC is a missense variant predicted to cause substitution of Serine by Phenylalanine at amino acid 203 (p.Ser203Phe). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00000085 (1 allele out of 1,179,946), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.344, which was neither above nor below the thresholds for PP3 (≥ 0.644) or BP4 (≤ 0.290), predicting a damaging or benign impact on MYOC function.The Ser203Phe protein had similar secretion levels to wild type myocilin protein in this study (PMID: 16466712). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in participants of the control cohorts. 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, adapted from PMID: 32720330) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v2.0.0, 5 Dec 2024): BS3_Moderate, PM2_Supporting

PM2_Supporting

The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.00000085 (1 allele out of 1,179,946), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles.

BS3_Supporting

Applied at the BS3_Moderate level. The Ser203Phe protein had similar secretion levels to wild type myocilin protein in this study (PMID: 16466712). The assay met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function.

The S203F protein is secreted. The assay in this study meets the OddsPath threshold for BS3_Moderate (< 0.23) PubMed:16466712

PM5

No other LP or P missense variants at this amino acid residue have been identified.

PM4

This variant does not cause a protein length change.

BA1

This criterion was not met as PM2_Supporting has been met.

BS1

This criterion was not met as PM2_Supporting has been met.

BP4

The REVEL score = 0.344, which did not meet the ≤ 0.290 threshold required for BP4.

BP7

This is not an intronic, synonymous or non-coding variant.

PS4

This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in participants of the control cohorts.

PS2

This variant has not been identified de novo.

PS1

An established LP or P variant causing this same amino acid change has not been identified.

PS3

This criterion was not met as BS3_Moderate has been met.

PP1

No segregations have been reported for this variant.

PP3

The REVEL score = 0.344, which did not meet the ≥ 0.644 threshold required for PP3.

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.