Variant: NM_000261.2:c.1255A>G

CA343724143

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 444e4614-b60e-47ad-aa24-9a7903e1a7b3

Approved on: 2023-08-08

Published on: 2023-08-08

HGVS expressions

NM_000261.2:c.1255A>G
NC_000001.11:g.171636185T>C
CM000663.2:g.171636185T>C
NC_000001.10:g.171605325T>C
CM000663.1:g.171605325T>C
NC_000001.9:g.169871948T>C
NG_008859.1:g.21449A>G
ENST00000037502.11:c.1255A>G
ENST00000637303.1:c.235-2445T>C
ENST00000638471.1:c.*593A>G
ENST00000037502.10:c.1255A>G
ENST00000614688.1:c.*219A>G
NM_000261.1:c.1255A>G

Uncertain Significance

• Met criteria codes: PM2_Supporting PP3

• Not Met criteria codes: BS3 BS1 BP7 BP4 PS2 PS1 PS3 PS4 PM5 PM4 BA1 PM6 PP1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1255A>G variant in MYOC is a missense variant predicted to cause substitution of Threonine by Alanine at amino acid 419 (p.Thr419Ala). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.000008791 (1 allele out of 113,758), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.873, 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. 4 individuals with POAG have been reported carrying this variant (PMID: 30816137, Souzeau et al, 2021 and Albuainain et al, 2021). However, as they each also carry the pathogenic Gln368Ter variant (ClinVar ID:7949, classified pathogenic by the ClinGen Glaucoma VCEP), the role of Thr419Ala could not be established, thus probands were not included and PS4 was not met. In summary, this variant met the criteria to receive a score of 2 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PM2_Supporting

Met criteria codes

• PM2_Supporting: The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.000008791 (1 allele out of 113,758), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
• PP3: The REVEL score = 0.873, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on 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.
• BP4: This criterion was not met as PP3 has been met.
• 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.
• PS4: 4 individuals with POAG have been reported carrying this variant (PMID: 30816137, Souzeau et al, 2021 and Albuainain et al, 2021). However, as they each also carry the pathogenic Gln368Ter variant (ClinVar ID:7949, classified pathogenic by the ClinGen Glaucoma VCEP), the role of Thr419Ala could not be established, thus probands were not included and PS4 was not met.
• PM5: No other missense variants at this amino acid residue have been identified.
• 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.