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.1258A>T (p.Asn420Tyr)

CA1244054

1306862 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b6edaf6e-142a-4ca2-a0b1-96101bc019e8

Approved on: 2022-12-14

Published on: 2022-12-14

HGVS expressions

NM_000261.2:c.1258A>T

NM_000261.2(MYOC):c.1258A>T (p.Asn420Tyr)

NC_000001.11:g.171636182T>A

CM000663.2:g.171636182T>A

NC_000001.10:g.171605322T>A

CM000663.1:g.171605322T>A

NC_000001.9:g.169871945T>A

NG_008859.1:g.21452A>T

ENST00000037502.11:c.1258A>T

ENST00000637303.1:c.235-2448T>A

ENST00000638471.1:c.*596A>T

ENST00000037502.10:c.1258A>T

ENST00000614688.1:c.*222A>T

NM_000261.1:c.1258A>T

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

BA1 BS3 BS1 BP4 BP7 PS4 PS2 PS1 PS3 PP1 PP3 PM6 PM2 PM5 PM4

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1258A>T variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Tyrosine at amino acid 420 (p.Asn420Tyr). The highest minor allele frequency of this variant was in the European (non-Finnish) population of gnomAD (v2.1.1) = 0.0001393 (18 alleles out of 129,188), which did not meet the PM2_Supporting allele frequency threshold (≤ 0.0001) or the BS1 allele frequency threshold (≥ 0.001). The REVEL score = 0.566, 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. 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 (Hewitt et al, pers. comm.), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification 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): none

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 European (non-Finnish) population of gnomAD (v2.1.1) = 0.0001393 (18 alleles out of 129,188), which did not meet the ≥ 0.001 threshold set for BS1.

BP4

The REVEL score = 0.566, which did not meet the ≤ 0.15 threshold required for BP4.

BP7

This is not a synonymous or non-coding variant.

PS4

Only 1 proband with POAG had been reported (Hewitt et al, pers. comm.), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting.

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

No functional evidence has been found for this variant.

PP1

No segregations have been reported for this variant.

PP3

The REVEL score = 0.566, which did not meet the ≥ 0.7 threshold for PP3.

PM6

This variant has not been identified de novo.

PM2

PM5

PM5_Supporting could not be applied to this variant as no other missense variants at this amino acid residue have been identified in affected individuals.

PM4

This variant does not cause a protein length change.

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.