Variant: NM_000261.2(MYOC):c.365G>T (p.Gly122Val)

CA343718552

1302992 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 196b22b0-f2f5-4fc6-a399-b9c89bb23124

Approved on: 2023-05-03

Published on: 2023-05-03

HGVS expressions

NM_000261.2:c.365G>T
NM_000261.2(MYOC):c.365G>T (p.Gly122Val)
NC_000001.11:g.171652247C>A
CM000663.2:g.171652247C>A
NC_000001.10:g.171621387C>A
CM000663.1:g.171621387C>A
NC_000001.9:g.169888010C>A
NG_008859.1:g.5387G>T
ENST00000037502.11:c.365G>T
ENST00000638471.1:c.130+235G>T
ENST00000037502.10:c.365G>T
ENST00000614688.1:c.365G>T
NM_000261.1:c.365G>T

Uncertain Significance

• Met criteria codes: PM2_Supporting BP4

• Not Met criteria codes: BS3 BS1 BP7 PS4 PS2 PS1 PS3 PM5 PM4 BA1 PM6 PP1 PP3

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.365G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 122 (p.Gly122Val). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002893 (1 allele out of 34,570), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.062, which met the ≤ 0.15 threshold for BP4, suggesting 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. Only 1 proband with JOAG had been reported (pers. comm. GeneDX), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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, PM2_Supporting.

Met criteria codes

• PM2_Supporting: The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002893 (1 allele out of 34,570), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
• BP4: The REVEL score = 0.062, which met the ≤ 0.15 threshold for BP4, 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 PM2_Supporting has been met.
• BP7: This is not a synonymous or non-coding variant.
• PS4: Only 1 proband with JOAG had been reported (pers. comm. GeneDX), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.
• PS2: This variant has not been identified de novo.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PS3: No functional evidence has been found for this variant.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variants at the same amino acid residue (c.365G>C, p.Gly122Ala, PMID: Yadav et al, 2022, Pre-print and c.365G>A, p.Gly122Asp, ClinVarID: 1048923) were not classified as likely pathogenic or pathogenic.
• PM4: This variant does not cause a protein length change.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PM6: This variant has not been identified de novo.
• PP1: No segregations have been reported for this variant.
• PP3: This criterion was not met as BP4 has been met.