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(MYOC):c.975G>A (p.Thr325=)

CA1244108

293711 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: aa0c6cf7-663b-40a9-8c67-e48a4370d33d

HGVS expressions

NM_000261.2:c.975G>A
NM_000261.2(MYOC):c.975G>A (p.Thr325=)
NC_000001.11:g.171636465C>T
CM000663.2:g.171636465C>T
NC_000001.10:g.171605605C>T
CM000663.1:g.171605605C>T
NC_000001.9:g.169872228C>T
NG_008859.1:g.21169G>A
ENST00000037502.11:c.975G>A
ENST00000637303.1:c.235-2165C>T
ENST00000638471.1:c.*313G>A
ENST00000037502.10:c.975G>A
ENST00000614688.1:c.975G>A
NM_000261.1:c.975G>A

Benign

Met criteria codes 4
BA1 BS3_Supporting BP7 BP4
Not Met criteria codes 11
PM5 PM4 PS2 PS1 PS3 PS4 PM6 PM2 BS1 PP1 PP3

Evidence Links 1

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.975G>A variant in MYOC is a synonymous variant (p.Thr325=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.08643, which met the ≥ 0.01 threshold set for BA1 (2,157 alleles out of 24,956 which meets the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.008 which met the ≤ 10 threshold for BP4, and the GERP score = -11.5 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. A previous study (PMID: 35196929) demonstrated that the Thr325= protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function. As BA1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant was classified as benign (BA1 is a stand-alone criterion for a benign level of pathogenicity) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP: BA1, BP4, BP7, BS3_Supporting
Met criteria codes
BA1
The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) =0.08643, which met the ≥0.01 threshold set for BA1 (2,157 alleles out of 24,956, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
BS3_Supporting
A previous study (PMID: 35196929) demonstrated that the Thr325= protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function.
The Thr325= protein secreted and is soluble. This study meets the OddsPath threshold for BS3_Supporting (< 0.23). PubMed:35196929
BP7
This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -11.5 (threshold <0), indicating a lack of conservation at this site.
BP4
The CADD score (v1.6) = 0.008, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.
Not Met criteria codes
PM5
This is not a missense variant.
PM4
This variant does not cause a protein length change.
PS2
This variant has not been identified de novo.
PS1
This variant does not involve an amino acid change.
PS3
This criterion was not met as BS3_Supporting has been met.
PS4
Although probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PM6
This variant has not been identified de novo.
PM2
This criterion was not met as BA1 has been met.
BS1
This criterion was not met as BA1 has been met.
PP1
As BA1 was met, PP1 did not apply and segregations were not counted.
PP3
This is not a missense variant.
Approved on: 2023-11-14
Published on: 2023-11-14
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