NM_000261.2:c.42G>A

CA1244341

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 021d8f8f-273b-4129-9104-38d47aa4dab9

Approved on: 2023-05-03

Published on: 2023-05-03

HGVS expressions

NM_000261.2:c.42G>A
NC_000001.11:g.171652570C>T
CM000663.2:g.171652570C>T
NC_000001.10:g.171621710C>T
CM000663.1:g.171621710C>T
NC_000001.9:g.169888333C>T
NG_008859.1:g.5064G>A
ENST00000037502.11:c.42G>A
ENST00000638471.1:c.42G>A
ENST00000037502.10:c.42G>A
ENST00000614688.1:c.42G>A
NM_000261.1:c.42G>A

Uncertain Significance

• Met criteria codes: PS4_Supporting BP7 BP4 PM2_Supporting

• Not Met criteria codes: BS3 BS1 PS2 PS1 PS3 BA1 PP1 PP3 PM6 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.42G>A variant in MYOC is a synonymous variant (p.Glu14=). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002892 (1 allele out of 34,578), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 4.764 which met the ≤ 10 threshold for BP4, and the GERP score = -3.28 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 probands with juvenile open angle glaucoma have been reported carrying this variant (PMID: Yadav et al, 2022 pre-print), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 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): BP4, BP7, PS4_Supporting. PM2_Supporting.

Met criteria codes

• PS4_Supporting: 3 probands with JOAG have been reported carrying this variant (PMID: Yadav et al, 2022 pre-print), which met PS4_Supporting (≥ 2 probands).
• BP7: This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -3.28 (threshold < 0), indicating a lack of conservation at this site.
• BP4: The CADD score (v1.6) = 4.764, 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.
• PM2_Supporting: The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002892 (1 allele out of 34,578), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.

Not Met criteria codes

• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.
• 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP1: No segregations have been reported for this variant.
• PP3: This is not a missense variant.
• PM6: This variant has not been identified de novo.
• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.