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(MYOC):c.158T>C (p.Val53Ala)

CA1244317

631580 (ClinVar)

Gene: MYOC

Condition: juvenile open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 414f32f9-a590-4b3a-923d-855fdca2a912

HGVS expressions

NM_000261.2:c.158T>C

NM_000261.2(MYOC):c.158T>C (p.Val53Ala)

NC_000001.11:g.171652454A>G

CM000663.2:g.171652454A>G

NC_000001.10:g.171621594A>G

CM000663.1:g.171621594A>G

NC_000001.9:g.169888217A>G

NG_008859.1:g.5180T>C

ENST00000037502.11:c.158T>C

ENST00000638471.1:c.130+28T>C

ENST00000037502.10:c.158T>C

ENST00000614688.1:c.158T>C

NM_000261.1:c.158T>C

Uncertain Significance

BS3_Supporting

PS2 PS1 PS3 PS4 PP1 PP3 PM4 PM5 PM6 PM2 BA1 BS1 BP4 BP7

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.158T>C variant in MYOC is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 53 (p.Val53Ala). The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1) = 0.0008520 (17 alleles out of 19,954), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.369, 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 Val53Ala 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 for juvenile or primary open angle glaucoma have been identified 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 -1 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) : BS3_Supporting

BS3_Supporting

A previous study (PMID: 35196929) demonstrated that the Val53Ala 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 V53A protein is secreted and soluble. This study meets the OddsPath threshold for BS3_Supporting (< 0.48). PubMed:35196929

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

This criterion was not met as BS3_Supporting has been met.

PS4

Although multiple probands with POAG or JOAG have 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

The REVEL score = 0.369, which did not meet the ≥ 0.7 threshold for PP3.

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.157G>A, p.Val53Met, PMID: 33793440) was not classified as likely pathogenic or pathogenic.

PM6

This variant has not been identified de novo.

PM2

The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1)= 0.0008520 (17 alleles out of 19,954), which did not meet the ≤ 0.0001 threshold set for PM2_Supporting.

BA1

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

BS1

The highest minor allele frequency of this variant was in the East Asian population of gnomAD (v2.1.1)= 0.0008520 (17 alleles out of 19,954), which did not meet the ≥0.001 threshold set for BS1.

BP4

The REVEL score = 0.369, which did not meet the ≤ 0.15 threshold required for BP4.

BP7

This is not a synonymous or non-coding variant.

Approved on: 2023-11-14

Published on: 2023-11-14

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.