Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

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

CA343724143

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

PM2_Supporting PP3

BA1 BS3 BS1 BP4 BP7 PS2 PS1 PS3 PS4 PP1 PM6 PM5 PM4

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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

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.

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.

BP4

This criterion was not met as PP3 has been met.

BP7

This is not a synonymous or non-coding variant.

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.

PP1

No segregations have been reported for this variant.

PM6

This variant has not been identified de novo.

PM5

No other missense variants at this amino acid residue have been identified.

PM4

This variant does not cause a protein length change.

Approved on: 2023-08-08

Published on: 2023-08-08

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