Variant: NM_000261.2:c.752T>C

CA343726262

1342196 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 4c28aa89-61ff-4446-8824-3254caef54d3

Approved on: 2022-02-21

Published on: 2022-07-11

HGVS expressions

NM_000261.2:c.752T>C
NC_000001.11:g.171636688A>G
CM000663.2:g.171636688A>G
NC_000001.10:g.171605828A>G
CM000663.1:g.171605828A>G
NC_000001.9:g.169872451A>G
NG_008859.1:g.20946T>C
ENST00000037502.11:c.752T>C
ENST00000637303.1:c.235-1942A>G
ENST00000638471.1:c.*90T>C
ENST00000037502.10:c.752T>C
ENST00000614688.1:c.752T>C
NM_000261.1:c.752T>C
NM_000261.2(MYOC):c.752T>C (p.Val251Ala)

Likely Pathogenic

• Met criteria codes: PP3 PP1_Strong PS4_Supporting PM2_Supporting PS2_Moderate

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

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.752T>C variant in MYOC is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 251 (p.Val251Ala). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.839, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. 17 segregations in 3 families with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 32937162, 23517641 and Pasutto pers. comm.), which fulfilled PP1_Strong (≥ 7 meioses in >1 family). 3 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 32937162, 23517641 and Pasutto pers. comm.), which met PS4_Supporting (≥ 2 probands). One of these was a confirmed de novo proband with JOAG (PMID: 23517641) (PS2_Moderate). In summary, this variant met the criteria to receive a score of 9 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS2_Moderate, PP3, PS4_Supporting, PM2_Supporting.

Met criteria codes

• PP3: The REVEL score = 0.839, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• PP1_Strong: 17 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 32937162, 23517641 and Pasutto pers. comm.), which fulfilled PP1_Strong (≥7 meioses in >1 family).
• PS4_Supporting: 3 probands with JOAG or POAG have been reported (PMIDs: 32937162, 23517641 and Pasutto pers. comm.) carrying this variant, which met PS4_Supporting (≥ 2 probands).
• PM2_Supporting: This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
• PS2_Moderate: 1 confirmed de novo proband with JOAG has been identified.

Not Met criteria codes

• BP4: This criterion was not met as PP3 has been met.
• BP7: This is not a synonymous or non-coding variant.
• PM6: This criterion was not met as PS2 has been met.
• PM5: No other missense variants at this amino acid residue have been identified.
• PM4: This variant does not cause a protein length change.
• 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.