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.1441C>T

CA1244022

1686786 (ClinVar)

Gene: MYOC (HGNC:4653)

Condition: open-angle glaucoma (MONDO:0005338)

Inheritance Mode: Autosomal dominant inheritance

UUID: bf05c3e4-02c8-4fe4-83d8-8fbebe319aba

Approved on: 2026-02-05

Published on: 2026-02-05

HGVS expressions

NM_000261.2:c.1441C>T

NC_000001.11:g.171635999G>A

CM000663.2:g.171635999G>A

NC_000001.10:g.171605139G>A

CM000663.1:g.171605139G>A

NC_000001.9:g.169871762G>A

NG_008859.1:g.21635C>T

ENST00000037502.11:c.1441C>T

ENST00000637303.1:c.235-2631G>A

ENST00000638471.1:c.*779C>T

ENST00000037502.10:c.1441C>T

ENST00000614688.1:c.*405C>T

NM_000261.1:c.1441C>T

Uncertain Significance

PP3 PM2_Supporting

PS2 PS1 PS4 PS3 BP4 BP7 PP1 BA1 PM4 PM5 BS3 BS1

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.1441C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Serine at amino acid 481 (p.Pro481Ser). The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00008911 (4 alleles out of 44,888), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles. The REVEL score = 0.684, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function. The Pro481Ser protein was assessed in an assay (PMID: 35196929), however, the results for this protein were inconsistent and not included as evidence. Only 1 proband with primary open angle glaucoma had been reported (PMID: 15534471), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 2 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): PP3, PM2_Supporting.

PP3

The REVEL score = 0.684, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on MYOC function.

PM2_Supporting

The highest minor allele frequency of this variant was in the East Asian genetic ancestry group of gnomAD (v4.1.0) = 0.00008911 (4 alleles out of 44,888), which met the ≤ 0.0001 threshold set for PM2_Supporting in a genetic ancestry group of at least 10,000 alleles.

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.

PS4

Only 1 proband with POAG had been reported (PMID: 15534471), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

PS3

The Pro481Ser protein was assessed in an assay (PMID: 35196929), however, the results for this protein were inconsistent and not included as evidence.

The results for the Pro481Ser protein were inconsistent and not included as evidence. PubMed:35196929

BP4

This criterion was not met as PP3 has been met.

BP7

This criterion did not apply to this variant.

PP1

No segregations have been reported for this variant.

BA1

This criterion was not met as PM2_Supporting has been met.

PM4

This criterion did not apply to this variant.

PM5

PM5_Supporting could not be applied to this novel missense variant as although it did meet PP3, the Grantham score was lower (= 74) than the score for the different missense change at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (c.1442C>T, p.Pro481Leu, Grantham score =98, ClinVar ID: 1686789).

BS3

The Pro481Ser protein was assessed in an assay (PMID: 35196929), however, the results for this protein were inconsistent and not included as evidence.

The results for the Pro481Ser protein were inconsistent and not included as evidence. PubMed:35196929

BS1

This criterion was not met as PM2_Supporting has been met.

Curation History

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