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.1486A>C

CA343722900

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bff761ab-f657-4885-a167-de06974449df

Approved on: 2023-02-15

Published on: 2023-02-15

HGVS expressions

NM_000261.2:c.1486A>C

NC_000001.11:g.171635954T>G

CM000663.2:g.171635954T>G

NC_000001.10:g.171605094T>G

CM000663.1:g.171605094T>G

NC_000001.9:g.169871717T>G

NG_008859.1:g.21680A>C

ENST00000037502.11:c.1486A>C

ENST00000637303.1:c.235-2676T>G

ENST00000638471.1:c.*824A>C

ENST00000037502.10:c.1486A>C

ENST00000614688.1:c.*450A>C

NM_000261.1:c.1486A>C

Uncertain Significance

PM2_Supporting PP3

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

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1486A>C variant in MYOC is a missense variant predicted to cause substitution of Threonine by Proline at amino acid 496 (p.Thr496Pro). 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 = 0.704, 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 primary open angle glaucoma had been reported (PMID: 33793440), 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting

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.

PP3

The REVEL score = 0.704, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

BS3

No functional evidence has been found for this variant.

BS1

This criterion was not met as PM2_Supporting has been met.

BP7

This is not a synonymous or non-coding variant.

BP4

This criterion was not met as PP3 has been met.

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.

PS4

Only 1 proband with POAG had been reported (PMID: 33793440), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

BA1

This criterion was not met as PM2_Supporting has been met.

PP1

No segregations have been reported for this variant.

PM5

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

PM4

This variant does not cause a protein length change.

PM6

This variant has not been identified de novo.

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