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.976G>A

CA343725270

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7d3c820d-0e06-4153-94cf-0299999c3a75

HGVS expressions

NM_000261.2:c.976G>A

NC_000001.11:g.171636464C>T

CM000663.2:g.171636464C>T

NC_000001.10:g.171605604C>T

CM000663.1:g.171605604C>T

NC_000001.9:g.169872227C>T

NG_008859.1:g.21170G>A

ENST00000037502.11:c.976G>A

ENST00000637303.1:c.235-2166C>T

ENST00000638471.1:c.*314G>A

ENST00000037502.10:c.976G>A

ENST00000614688.1:c.976G>A

NM_000261.1:c.976G>A

Uncertain Significance

PP1 PP3 PM2_Supporting

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

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.976G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 326 (p.Gly326Ser). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.00003267 (1 allele out of 30,608), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.869, 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. 3 segregations in 1 family, with primary open angle glaucoma (POAG), have been reported (PMID: 22879734), which fulfilled PP1 (3-4 meioses). Only 1 proband with POAG had been reported (PMID: 22879734), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1, PP3, PM2_Supporting

PP1

3 segregations in 1 family, with primary open angle glaucoma (POAG), have been reported (PMID: 22879734), which fulfilled PP1 (3-4 meioses).

PP3

The REVEL score = 0.869, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

PM2_Supporting

The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.00003267 (1 allele out of 30,608), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.

PS2

This variant has not been identified de novo.

PS3

No functional evidence has been found for this variant.

PS1

An established pathogenic variant causing this same amino acid change has not been identified.

PS4

Only 1 proband with POAG had been reported (PMID: 22879734), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

BA1

This criterion was not met as PM2_Supporting has been met.

PM6

This variant has not been identified de novo.

BS3

No functional evidence has been found for this variant.

BS1

This criterion was not met as PM2_Supporting has been met.

PM4

This variant does not cause a protein length change.

PM5

PM5_Supporting could not be applied to this novel missense variant as although it did meet PP3, the Grantham score was lower (= 56) than the score for the different missense change at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (c.976G>C, p.Gly326Arg, Grantham score = 125).

BP4

This criterion was not met as PP3 has been met.

BP7

This is not a synonymous or non-coding variant.

Approved on: 2023-02-15

Published on: 2023-02-15

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