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.1435T>C

CA343723184

1173106 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 786c416b-efd1-4750-a177-474cd714da92

HGVS expressions

NM_000261.2:c.1435T>C

NC_000001.11:g.171636005A>G

CM000663.2:g.171636005A>G

NC_000001.10:g.171605145A>G

CM000663.1:g.171605145A>G

NC_000001.9:g.169871768A>G

NG_008859.1:g.21629T>C

ENST00000037502.11:c.1435T>C

ENST00000637303.1:c.235-2625A>G

ENST00000638471.1:c.*773T>C

ENST00000037502.10:c.1435T>C

ENST00000614688.1:c.*399T>C

NM_000261.1:c.1435T>C

NM_000261.2(MYOC):c.1435T>C (p.Tyr479His)

Uncertain Significance

PP3 PS4_Supporting PM2_Supporting

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

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1435T>C variant in MYOC is a missense variant predicted to cause substitution of Tyrosine by Histidine at amino acid 479 (p.Tyr479His). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.981, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. The study reporting functional evidence (PMID: 17615537) demonstrated that the Y479H protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. Only 1 segregation had been reported for open angle glaucoma (ClinVar: SCV001738398.1), not meeting the ≥ 3 segregations required for PP1. 3 probands with juvenile or primary open angle glaucoma have been reported carrying this variant (PMIDs: 23922489, 17615537 and ClinVar: SCV001738398.1), which met PS4_Supporting (≥ 2 probands). 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 juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP3, PS4_Supporting, PM2_Supporting

PP3

The REVEL score = 0.981, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

PS4_Supporting

3 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 23922489, 17615537 and ClinVar: SCV001738398.1), which met PS4_Supporting (≥ 2 probands).

PM2_Supporting

This variant was not found in any population of gnomAD (v2.1.1), meeting 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.

PS1

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

PS3

The study reporting functional evidence (PMID: 17615537) demonstrated that the Y479H protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.

BP4

This criterion was not met as PP3 has been met.

BP7

This is not a synonymous or non-coding variant.

BA1

This criterion was not met as PM2_Supporting has been met.

PP1

Only 1 segregation had been reported for open angle glaucoma (ClinVar: SCV001738398.1), not meeting the ≥ 3 segregations required for PP1.

PM5

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

PM4

This variant does not cause a protein length change.

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.

Approved on: 2023-05-03

Published on: 2023-05-03

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