Variant: NM_000261.2(MYOC):c.1196G>T (p.Gly399Val)

CA119182

7957 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 7543f7e0-692c-4ce1-867a-c57c1f97d9a2

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000261.2:c.1196G>T
NM_000261.2(MYOC):c.1196G>T (p.Gly399Val)
NC_000001.11:g.171636244C>A
CM000663.2:g.171636244C>A
NC_000001.10:g.171605384C>A
CM000663.1:g.171605384C>A
NC_000001.9:g.169872007C>A
NG_008859.1:g.21390G>T
ENST00000037502.11:c.1196G>T
ENST00000637303.1:c.235-2386C>A
ENST00000638471.1:c.*534G>T
ENST00000037502.10:c.1196G>T
ENST00000614688.1:c.*160G>T
NM_000261.1:c.1196G>T

Uncertain Significance

• Met criteria codes: PP1_Moderate PP3

• Not Met criteria codes: PM6 PM2 PM5 PM4 BA1 BS1 BS3 BP7 BP4 PS1 PS2 PS3 PS4

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.1196G>T variant in MYOC is a missense variant predicted to cause substitution of Glycine by Valine at amino acid 399 (p.Gly399Val). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.0001156 (4 alleles out of 34,592), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.968, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 10 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 11774072), which fulfilled PP1_Moderate (5-6 meioses). Although a proband with JOAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of 3 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): PP1_Moderate, PP3.

Met criteria codes

• PP1_Moderate: 10 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 11774072), which fulfilled PP1_Moderate (5-6 meioses).
• PP3: The REVEL score = 0.968, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

Not Met criteria codes

• PM6: This variant has not been identified de novo.
• PM2: The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.0001156 (4 alleles out of 34,592), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1196G>A, p.Gly399Asp, PMID: 17562996) was not classified as likely pathogenic or pathogenic.
• PM4: This variant does not cause a protein length change.
• BA1: This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).
• BS1: The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.0001156 (4 alleles out of 34,592), which did not meet the ≥ 0.001 threshold nor the ≥5 alleles necessary to meet BS1.
• BS3: No functional evidence has been found for this variant.
• BP7: This is not a synonymous or non-coding variant.
• BP4: This criterion was not met as PP3 has been met.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PS2: This variant has not been identified de novo.
• PS3: No functional evidence has been found for this variant.
• PS4: Although a proband with JOAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.