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Variant: NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)

CA119171

7948 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 924d6dc0-3570-496f-a90d-2cb4cd205f2f

HGVS expressions

NM_000261.2:c.1109C>T
NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)
NC_000001.11:g.171636331G>A
CM000663.2:g.171636331G>A
NC_000001.10:g.171605471G>A
CM000663.1:g.171605471G>A
NC_000001.9:g.169872094G>A
NG_008859.1:g.21303C>T
ENST00000037502.11:c.1109C>T
ENST00000637303.1:c.235-2299G>A
ENST00000638471.1:c.*447C>T
ENST00000037502.10:c.1109C>T
ENST00000614688.1:c.*73C>T
NM_000261.1:c.1109C>T

Pathogenic

Met criteria codes 5
PP1_Strong PS3_Moderate PM2_Supporting PS4 PP3
Not Met criteria codes 10
BA1 BS3 BS1 BP7 BP4 PS2 PS1 PM6 PM5 PM4

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1109C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 370 (p.Pro370Leu). 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 = 0.89, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Pro370Leu protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (≥7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting
Met criteria codes
PP1_Strong
21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (≥7 meioses in >1 family). There were many more family studies published than presented here.
PS3_Moderate
A previous study (PMID: 16466712) demonstrated that the Pro370Leu protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein 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
15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (≥ 15 probands). There were many more probands published than presented here.
PP3
The REVEL score = 0.89, 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.
BS3
This criterion was not met as PS3_Moderate has been met.
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.
PM6
This variant has not been identified de novo.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
Approved on: 2022-03-07
Published on: 2022-07-11
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