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.1267A>C

CA343724106

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c1ae08f5-b921-414e-a495-10277f618505

HGVS expressions

NM_000261.2:c.1267A>C

NC_000001.11:g.171636173T>G

CM000663.2:g.171636173T>G

NC_000001.10:g.171605313T>G

CM000663.1:g.171605313T>G

NC_000001.9:g.169871936T>G

NG_008859.1:g.21461A>C

ENST00000037502.11:c.1267A>C

ENST00000637303.1:c.235-2457T>G

ENST00000638471.1:c.*605A>C

ENST00000037502.10:c.1267A>C

ENST00000614688.1:c.*231A>C

NM_000261.1:c.1267A>C

Uncertain Significance

PP3 PM2_Supporting

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

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.1267A>C variant in MYOC is a missense variant predicted to cause substitution of Lysine by Glutamine at amino acid 423 (p.Lys423Gln). 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 REVEL score = 0.795, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 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: 35946471), 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) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting.

PP3

The REVEL score = 0.795, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on 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.

PS4

Only 1 proband with JOAG had been reported (PMID: 35946471), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

PS2

This variant has not been identified de novo.

PS1

An established pathogenic variant causing this same amino acid change has not been identified.

PS3

No functional evidence has been found for this variant.

PP1

No segregations have been reported for 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 (= 53) 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.1267A>G, p.Lys423Glu, Grantham score=56).

PM4

This variant does not cause a protein length change.

PM6

This variant has not been identified de novo.

BA1

This criterion was not met as PM2_Supporting has been met.

BS3

No functional evidence has been found for this variant.

BS1

This criterion was not met as PM2_Supporting has been met.

BP4

This criterion was not met as PP3 has been met.

BP7

This is not a synonymous or non-coding variant.

Approved on: 2023-07-05

Published on: 2023-07-05

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