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  • See Evidence submitted by expert panel for details.

Variant: NM_000261.2(MYOC):c.1430T>G (p.Ile477Ser)

CA119174

7950 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 6e296ba8-41a9-4f53-b189-0d71102717a4
Approved on: 2022-05-10
Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1430T>G
NM_000261.2(MYOC):c.1430T>G (p.Ile477Ser)
NC_000001.11:g.171636010A>C
CM000663.2:g.171636010A>C
NC_000001.10:g.171605150A>C
CM000663.1:g.171605150A>C
NC_000001.9:g.169871773A>C
NG_008859.1:g.21624T>G
ENST00000037502.11:c.1430T>G
ENST00000637303.1:c.235-2620A>C
ENST00000638471.1:c.*768T>G
ENST00000037502.10:c.1430T>G
ENST00000614688.1:c.*394T>G
NM_000261.1:c.1430T>G

Uncertain Significance

Met criteria codes 3
PS3_Supporting PP1_Moderate PM2_Supporting
Not Met criteria codes 12
BS3 BS1 PS2 PS1 PS4 BP7 BP4 BA1 PP3 PM4 PM5 PM6

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1430T>G variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Serine at amino acid 477 (p.Ile477Ser). 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 = 0.646, 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. A previous study (PMID: 10545602) demonstrated that the Ile477Ser protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9328473), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 9328473), 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, PS3_Supporting, PM2_Supporting
Met criteria codes
PS3_Supporting
A previous study (PMID: 10545602) demonstrated that the Ile477Ser protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function.

PP1_Moderate
20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9328473), which fulfilled PP1_Moderate (≥5 meioses in ≥1 family, but not the ≥7 meioses in >1 family for the strong criterion).
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
BS3
This criterion was not met as PS3_Supporting has been met.
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.
PS4
Only 1 proband with JOAG had been reported (PMID: 9328473), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
BP7
This is not a synonymous or non-coding variant.
BP4
The REVEL score = 0.646, which did not meet the ≤ 0.15 threshold required for BP4.
BA1
This criterion was not met as PM2_Supporting has been met.
PP3
The REVEL score = 0.646, 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 novel missense variant as it did not meet PP3 and the Grantham score was lower (=142) than the score for the different missense change at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (1430T>A, Ile477Asn, Grantham score = 149, ClinVarID: ).
PM6
This variant has not been identified de novo.
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