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Variant: NM_000261.2:c.1364C>A

CA343723562

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: f6b6b529-db5d-4217-9fb4-dc6e8209689f

HGVS expressions

NM_000261.2:c.1364C>A
NC_000001.11:g.171636076G>T
CM000663.2:g.171636076G>T
NC_000001.10:g.171605216G>T
CM000663.1:g.171605216G>T
NC_000001.9:g.169871839G>T
NG_008859.1:g.21558C>A
ENST00000037502.11:c.1364C>A
ENST00000637303.1:c.235-2554G>T
ENST00000638471.1:c.*702C>A
ENST00000037502.10:c.1364C>A
ENST00000614688.1:c.*328C>A
NM_000261.1:c.1364C>A

Uncertain Significance

Met criteria codes 3
PM2_Supporting PP1_Moderate PP3
Not Met criteria codes 12
BA1 BP7 BP4 BS3 BS1 PS2 PS1 PS3 PS4 PM5 PM4 PM6

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.1364C>A variant in MYOC is a missense variant predicted to cause substitution of Threonine by Lysine at amino acid 455 (p.Thr455Lys). 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 = 0.938, 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. 10 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 18067072), which fulfilled PP1_Moderate (5-6 meioses). Only 1 proband with JOAG had been reported (PMID: 18067072), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 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): PP1_Moderate, PP3, 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.
PP1_Moderate
10 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 18067072), which fulfilled PP1_Moderate (5-6 meioses).
PP3
The REVEL score = 0.938, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
Not Met criteria codes
BA1
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.
BS3
No functional evidence has been found for this variant.
BS1
This criterion was not met as PM2_Supporting 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 JOAG had been reported (PMID: 18067072), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
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.
Approved on: 2023-08-08
Published on: 2023-08-08
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