Variant: NM_000261.2(MYOC):c.1111T>C (p.Tyr371His)

CA10583955

242274 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 08f4dcd1-5d42-4884-a90f-c6919929f4e5

Approved on: 2023-08-08

Published on: 2023-08-08

HGVS expressions

NM_000261.2:c.1111T>C
NM_000261.2(MYOC):c.1111T>C (p.Tyr371His)
NC_000001.11:g.171636329A>G
CM000663.2:g.171636329A>G
NC_000001.10:g.171605469A>G
CM000663.1:g.171605469A>G
NC_000001.9:g.169872092A>G
NG_008859.1:g.21305T>C
ENST00000037502.11:c.1111T>C
ENST00000637303.1:c.235-2301A>G
ENST00000638471.1:c.*449T>C
ENST00000037502.10:c.1111T>C
ENST00000614688.1:c.*75T>C
NM_000261.1:c.1111T>C

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

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

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.1111T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 371 (p.Tyr371His). 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 = 0.875, 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. Only 2 segregations had been reported for juvenile open angle glaucoma, including 1 proband (Teruya et al, 2008), not meeting the ≥ 3 segregations required for PP1 or the ≥ 2 probands threshold required to meet PS4_Supporting. These individuals are reported in ClinVar (SCV000268698.1). 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 juvenile 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

• PP3: The REVEL score = 0.875, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
• 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.

Not Met criteria codes

• PS4: Only 1 proband with JOAG had been reported (Teruya et al, 2008), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. This proband was also reported in ClinVar (SCV000268698.1).
• 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.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PP1: Only 2 segregations had been reported for juvenile open angle glaucoma (Teruya et al, 2008), not meeting the ≥ 3 segregations required for PP1.
• PM6: This variant has not been identified de novo.
• PM5: PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1111T>G, p.Tyr371Asp) was not classified as likely pathogenic or pathogenic.
• PM4: This variant does not cause a protein length change.
• 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 BP4 has been met.