Variant: NM_000261.2(MYOC):c.477A>G (p.Leu159=)

CA1244271

293717 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: a850514d-d70f-4e82-a441-eff1039ef137

HGVS expressions

NM_000261.2:c.477A>G
NM_000261.2(MYOC):c.477A>G (p.Leu159=)
NC_000001.11:g.171652135T>C
CM000663.2:g.171652135T>C
NC_000001.10:g.171621275T>C
CM000663.1:g.171621275T>C
NC_000001.9:g.169887898T>C
NG_008859.1:g.5499A>G
ENST00000037502.11:c.477A>G
ENST00000638471.1:c.130+347A>G
ENST00000037502.10:c.477A>G
ENST00000614688.1:c.477A>G
NM_000261.1:c.477A>G

Benign

• Met criteria codes: BA1 BP4

• Not Met criteria codes: BS3 BS1 BP7 PS2 PS1 PS3 PS4 PP3 PP1 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.477A>G variant in MYOC is a synonymous variant (p.Leu159=). The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07458, which met the ≥ 0.01 threshold set for BA1 (1,860 alleles out of 24,938, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The CADD score (v1.6) = 6.353, 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. However, BP7 was not met as this variant had a GERP score = 4.49 (threshold <0), indicating conservation at this site. 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 (v1, 12 Oct 2021): BA1, BP4.

Met criteria codes

• BA1: The highest minor allele frequency of this variant was in the African/African-American population of gnomAD (v2.1.1) = 0.07458, which met the ≥ 0.01 threshold set for BA1 (1,860 alleles out of 24,938, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
• BP4: The CADD score (v1.6) = 6.353, 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

• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as BA1 has been met.
• BP7: Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 4.49 (threshold <0), indicating conservation at this site.
• PS2: This variant has not been identified de novo.
• PS1: This variant does not involve an amino acid change.
• PS3: No functional evidence has been found for this variant.
• PS4: Although probands with JOAG or POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
• PP3: This is not a missense variant.
• PP1: As BA1 was met, PP1 did not apply and segregations were not counted.
• 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.

Approved on: 2022-02-07

Published on: 2022-07-11