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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000261.2:c.468G>A

CA421939232

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e4b180c1-2dfc-47de-9211-467928201a9e

HGVS expressions

NM_000261.2:c.468G>A

NC_000001.11:g.171652144C>T

CM000663.2:g.171652144C>T

NC_000001.10:g.171621284C>T

CM000663.1:g.171621284C>T

NC_000001.9:g.169887907C>T

NG_008859.1:g.5490G>A

ENST00000037502.11:c.468G>A

ENST00000638471.1:c.130+338G>A

ENST00000037502.10:c.468G>A

ENST00000614688.1:c.468G>A

NM_000261.1:c.468G>A

Uncertain Significance

BP4 PM2_Supporting

BS3 BS1 BP7 BA1 PS4 PS2 PS1 PS3 PP1 PP3 PM5 PM4 PM6

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.468G>A variant in MYOC is a synonymous variant (p.Lys156=). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The CADD score (v1.6) = 7.948, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function. However, BP7 was not met as this variant had a GERP score = 3.22 (threshold < 0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with juvenile open angle glaucoma had been reported (PMID: Yadav et al, 2022, Pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 0 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4, PM2_Supporting.

BP4

The CADD score (v1.6) = 7.948, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.

PM2_Supporting

This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.

BS3

No functional evidence has been found for this variant.

BS1

This criterion was not met as PM2_Supporting has been met.

BP7

Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 3.22 (threshold < 0), indicating conservation at this site.

BA1

This criterion was not met as PM2_Supporting has been met.

PS4

Only 1 proband with JOAG had been reported (PMID: Yadav et al, 2022, Pre-print), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

PS2

This variant has not been identified de novo.

PS1

This variant does not involve an amino acid change.

PS3

No functional evidence has been found for this variant.

PP1

No segregations have been reported for this variant.

PP3

This is not a missense variant.

PM5

This is not a missense variant.

PM4

This variant does not cause a protein length change.

PM6

This variant has not been identified de novo.

Approved on: 2023-07-05

Published on: 2023-07-05

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