Evidence Repository
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.1339G>A

CA343723686

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 69e81adb-daf1-41b8-8e62-a2fe95addb6d
Approved on: 2023-04-04
Published on: 2023-04-04

HGVS expressions

NM_000261.2:c.1339G>A
NC_000001.11:g.171636101C>T
CM000663.2:g.171636101C>T
NC_000001.10:g.171605241C>T
CM000663.1:g.171605241C>T
NC_000001.9:g.169871864C>T
NG_008859.1:g.21533G>A
ENST00000037502.11:c.1339G>A
ENST00000637303.1:c.235-2529C>T
ENST00000638471.1:c.*677G>A
ENST00000037502.10:c.1339G>A
ENST00000614688.1:c.*303G>A
NM_000261.1:c.1339G>A

Uncertain Significance

Met criteria codes 1
PM2_Supporting
Not Met criteria codes 14
BP4 BP7 PS2 PS3 PS1 PS4 PP1 PP3 PM4 PM5 PM6 BA1 BS3 BS1

Evidence Links 0

Expert Panel

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.1339G>A variant in MYOC is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 447 (p.Ala447Thr). 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 = 0.254, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact 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: 23453510), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 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): PM2_Supporting.
Met criteria codes
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.
Not Met criteria codes
BP4
The REVEL score = 0.254, which did not meet the ≤ 0.15 threshold required for BP4.
BP7
This is not a synonymous or non-coding variant.
PS2
This variant has not been identified de novo.
PS3
No functional evidence has been found for this variant.
PS1
An established pathogenic variant causing this same amino acid change has not been identified.
PS4
Only 1 proband with POAG had been reported (PMID: 23453510), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
PP1
No segregations have been reported for this variant.
PP3
The REVEL score = 0.254, which did not meet the ≥ 0.7 threshold for PP3.
PM4
This variant does not cause a protein length change.
PM5
PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1340C>T, p.Ala447Val, PMID: 21815720) was not classified as likely pathogenic or pathogenic.
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.
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