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]

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Variant: NM_000261.2:c.34G>C

CA1244345

876089 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8eae89ac-b0f9-4a81-a04f-bdc1ba3f6f6c

HGVS expressions

NM_000261.2:c.34G>C

NC_000001.11:g.171652578C>G

CM000663.2:g.171652578C>G

NC_000001.10:g.171621718C>G

CM000663.1:g.171621718C>G

NC_000001.9:g.169888341C>G

NG_008859.1:g.5056G>C

ENST00000037502.11:c.34G>C

ENST00000638471.1:c.34G>C

ENST00000037502.10:c.34G>C

ENST00000614688.1:c.34G>C

NM_000261.1:c.34G>C

NM_000261.2(MYOC):c.34G>C (p.Gly12Arg)

Likely Benign

BS3_Supporting BS1

PM5 PM4 PS2 PS1 PS4 PS3 PM6 PM2 BA1 BP7 BP4 PP1 PP3

Evidence Links 1

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.34G>C variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 12 (p.Gly12Arg). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.008922, which met the ≥ 0.001 threshold set for BS1 (178 alleles out of 19 950, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.33, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 35196929) demonstrated that the Gly12Arg protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function. Although probands with primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -5 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Supporting

BS3_Supporting

A previous study (PMID: 35196929) demonstrated that the Gly12Arg protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Supporting (< 0.48), indicating that this variant did not impact protein function.

The G12R protein is secreted and soluble. This study meets the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:35196929

BS1

The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.008922, which met the ≥ 0.001 threshold set for BS1 (178 alleles out of 19 950, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).

PM5

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

PM4

This variant does not cause a protein length change.

PS2

This variant has not been identified de novo.

PS1

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

PS4

Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.

PS3

This criterion was not met as BS3_Supporting has been met.

PM6

This variant has not been identified de novo.

PM2

This criterion was not met as BS1 has been met.

BA1

This criterion was not met as BS1 has been met.

BP7

This is not a synonymous or non-coding variant.

BP4

The REVEL score = 0.33, which did not meet the ≤ 0.15 threshold required for BP4.

PP1

As BS1 was met, PP1 did not apply and segregations were not counted.

PP3

The REVEL score = 0.33 which did not meet the ≥ 0.7 threshold for PP3.

Approved on: 2023-11-14

Published on: 2023-11-14

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