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

UUID: aa0c6cf7-663b-40a9-8c67-e48a4370d33d

Approved on: 2023-11-14

Published on: 2023-11-14

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: BS3_Supporting BP4 BP7 BA1

• Not Met criteria codes: BS1 PS2 PS1 PS3 PS4 PP1 PP3 PM6 PM2 PM5 PM4

Expert Panel

Glaucoma VCEP

Criteria Specification Information

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

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

• 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.
• 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.
• 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.
• 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).

Not Met criteria codes

• BS1: This criterion was not met as BA1 has been met.
• 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.
• PP1: As BA1 was met, PP1 did not apply and segregations were not counted.
• PP3: This is not a missense variant.
• PM6: This variant has not been identified de novo.
• PM2: This criterion was not met as BA1 has been met.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.