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]

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Variant: NM_000261.2:c.1452G>A

CA421938581

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ca98206c-190d-4706-87c3-4473c409e130

Approved on: 2023-02-15

Published on: 2023-02-15

HGVS expressions

NM_000261.2:c.1452G>A

NC_000001.11:g.171635988C>T

CM000663.2:g.171635988C>T

NC_000001.10:g.171605128C>T

CM000663.1:g.171605128C>T

NC_000001.9:g.169871751C>T

NG_008859.1:g.21646G>A

ENST00000037502.11:c.1452G>A

ENST00000637303.1:c.235-2642C>T

ENST00000638471.1:c.*790G>A

ENST00000037502.10:c.1452G>A

ENST00000614688.1:c.*416G>A

NM_000261.1:c.1452G>A

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

PS4 PS2 PS1 PS3 BA1 PP1 PP3 PM6 PM2 PM5 PM4 BS3 BS1 BP7 BP4

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1452G>A variant in MYOC is a synonymous variant (p.Lys484=). The gnomAD (v2.1.1) database had poor genotype data for this genomic position and did not represent the population from which the variant has been reported (South Asian). Thus PM2_Supporting was not applied to this variant. Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.90, which did not meet the ≤ 10 threshold for BP4 and a GERP score = 4.88 (threshold <0), not meeting BP7 and indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with JOAG 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 juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): none

PS4

Although probands with JOAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.

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.

BA1

This criterion was not met as PM2_Supporting has been met.

PP1

No segregations have been reported for this variant.

PP3

This is not a missense variant.

PM6

This variant has not been identified de novo.

PM2

The gnomAD (v2.1.1) database had poor genotype data for this genomic position and did not represent the population from which the variant has been reported (South Asian). Thus PM2_Supporting was not applied to this variant.

PM5

This is not a missense variant.

PM4

This variant does not cause a protein length change.

BS3

No functional evidence has been found for this variant.

BS1

See comment for PM2_Supporting

BP7

Although this synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 4.88 (threshold <0), indicating conservation at this site.

BP4

Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.90, which does not meet the ≤ 10 threshold for BP4.

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