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(MYOC):c.1297T>C (p.Cys433Arg)

CA119181

7956 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 17a16a8f-7d35-4be9-9c5a-125f169a53f3

HGVS expressions

NM_000261.2:c.1297T>C

NM_000261.2(MYOC):c.1297T>C (p.Cys433Arg)

NC_000001.11:g.171636143A>G

CM000663.2:g.171636143A>G

NC_000001.10:g.171605283A>G

CM000663.1:g.171605283A>G

NC_000001.9:g.169871906A>G

NG_008859.1:g.21491T>C

ENST00000037502.11:c.1297T>C

ENST00000637303.1:c.235-2487A>G

ENST00000638471.1:c.*635T>C

ENST00000037502.10:c.1297T>C

ENST00000614688.1:c.*261T>C

NM_000261.1:c.1297T>C

Pathogenic

PM2_Supporting PP1_Strong PS3_Moderate PP3 PS4

BA1 BP7 BP4 BS3 BS1 PS2 PS1 PM4 PM5 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.1297T>C variant in MYOC is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 433 (p.Cys433Arg). 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 = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Cys433Arg protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. 23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands). In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting.

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.

PP1_Strong

23 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 10819638, 16936947, 12671463), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).

PS3_Moderate

A previous study (PMID: 16466712) demonstrated that the Cys433Arg protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.

PP3

The REVEL score = 0.913, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.

PS4

30 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 30484747, 10819638, 16936947, 12671463), which met PS4 (≥ 15 probands).

BA1

This criterion was not met as PM2_Supporting has been met.

BP7

This is not a synonymous or non-coding variant.

BP4

This criterion was not met as PP3 has been met.

BS3

This criterion was not met as PS3_Moderate has been met.

BS1

This criterion was not met as PM2_Supporting has been met.

PS2

This variant has not been identified de novo.

PS1

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

PM4

This variant does not cause a protein length change.

PM5

PM5_Supporting could not be applied to this variant as the other missense variant at the same amino acid residue (c.1298G>A, p.Cys433Tyr, Grantham score = 194, PMID: 33793440) had a higher Grantham score than this variant (Grantham score=180) and was not classified as likely pathogenic or pathogenic. This variant was used to apply PM5_Supporting to variant c.1298G>A, p.Cys433Tyr, PMID: 33793440 which is located at the same amino acid residue.

PM6

This variant has not been identified de novo.

Approved on: 2022-05-10

Published on: 2022-05-25

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