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.498G>C

CA421939121

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6f062353-4b17-4d27-99b4-e167b0c661e8

HGVS expressions

NM_000261.2:c.498G>C

NC_000001.11:g.171652114C>G

CM000663.2:g.171652114C>G

NC_000001.10:g.171621254C>G

CM000663.1:g.171621254C>G

NC_000001.9:g.169887877C>G

NG_008859.1:g.5520G>C

ENST00000037502.11:c.498G>C

ENST00000638471.1:c.130+368G>C

ENST00000037502.10:c.498G>C

ENST00000614688.1:c.498G>C

NM_000261.1:c.498G>C

Uncertain Significance

PM2_Supporting

BA1 BS3 BS1 BP7 BP4 PS2 PS1 PS3 PS4 PP1 PP3 PM5 PM4 PM6

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.498G>C variant in MYOC is a synonymous variant (p.Leu166=). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002891 (1 allele out of 34,592), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.96, which did not meet the ≤ 10 threshold for BP4 and a GERP score = 4.69 (threshold <0), not meeting BP7 and indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 17615537), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 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): PM2_Supporting

PM2_Supporting

The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002891 (1 allele out of 34,592), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.

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.

BP7

Although this synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 4.69 (threshold <0), indicating conservation at this site.

BP4

Although this synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a CADD score (v1.6) = 10.96, which does not meet the ≤ 10 threshold for BP4.

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

Only 1 proband with POAG had been reported (PMID: 17615537), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

PP1

No segregations have been reported for this variant.

PP3

This is not a missense variant.

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.

Approved on: 2023-02-15

Published on: 2023-02-15

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