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

CA1244299

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4ec4bd9b-8ff5-4e5c-a70e-d8aac39c172c

HGVS expressions

NM_000261.2:c.303A>G

NC_000001.11:g.171652309T>C

CM000663.2:g.171652309T>C

NC_000001.10:g.171621449T>C

CM000663.1:g.171621449T>C

NC_000001.9:g.169888072T>C

NG_008859.1:g.5325A>G

ENST00000037502.11:c.303A>G

ENST00000638471.1:c.130+173A>G

ENST00000037502.10:c.303A>G

ENST00000614688.1:c.303A>G

NM_000261.1:c.303A>G

Likely Benign

BP7 BP4

BA1 BS3 BS1 PS2 PS1 PS3 PS4 PP1 PP3 PM5 PM4 PM6 PM2

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.303A>G variant in MYOC is a synonymous variant (p.Gln101=). The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.0003608 (9 alleles out of 24,944), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.141 which met the ≤ 10 threshold for BP4, and the GERP score = -3.2 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although a proband with primary open angle glaucoma had 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 -2 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): BP4, BP7

BP7

This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -3.2 (threshold <0), indicating a lack of conservation at this site.

BP4

The CADD score (v1.6) = 0.414, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.

BA1

This variant did not meet the ≥ 0.01 minor allele frequency threshold in gnomAD (v2.1.1).

BS3

No functional evidence has been found for this variant.

BS1

The highest minor allele frequency of this variant was in the African/African American population of gnomAD (v2.1.1) = 0.0003608 (9 alleles out of 24,944), which did not meet the ≥ 0.001 threshold set for BS1.

PS2

This variant has not been identified de novo.

PS1

This variant does not involve an amino acid change.

PS3

No functional evidence has been found for this variant.

PS4

Although a proband with POAG had been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.

PP1

No segregations have been reported for this variant.

PP3

This criterion was not met as BP4 has been met.

PM5

This is not a missense variant.

PM4

This variant does not cause a protein length change.

PM6

This variant has not been identified de novo.

PM2

Approved on: 2022-11-10

Published on: 2022-11-10

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