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.1348A>G

CA343723649

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6f4c2c8c-7d79-41a5-99f8-459c04658b6b

HGVS expressions

NM_000261.2:c.1348A>G

NC_000001.11:g.171636092T>C

CM000663.2:g.171636092T>C

NC_000001.10:g.171605232T>C

CM000663.1:g.171605232T>C

NC_000001.9:g.169871855T>C

NG_008859.1:g.21542A>G

ENST00000037502.11:c.1348A>G

ENST00000637303.1:c.235-2538T>C

ENST00000638471.1:c.*686A>G

ENST00000037502.10:c.1348A>G

ENST00000614688.1:c.*312A>G

NM_000261.1:c.1348A>G

Uncertain Significance

PM2_Supporting

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

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.1348A>G variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Aspartic Acid at amino acid 450 (p.Asn450Asp). 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 = 0.605, 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. This variant has not yet been identified in a proband diagnosed with juvenile or primary open angle glaucoma, only in a participant with preperimetric primary open angle glaucoma, thus PS4 was not applied. 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

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.

PS3

No functional evidence has been found for this variant.

PS1

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

PS4

This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in a participant with preperimetric POAG.

PP1

No segregations have been reported for this variant.

PP3

The REVEL score = 0.605, which did not meet the ≥ 0.7 threshold for PP3.

BA1

This criterion was not met as PM2_Supporting has been met.

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.

PM4

This variant does not cause a protein length change.

PM5

PM5_Supporting could not be applied to this novel missense variant as it did not meet PP3, and the Grantham score was lower (= 23) than the score for the different missense change at the same amino acid residue determined to be likely pathogenic by the ClinGen Glaucoma VCEP (c.1348A>T, p.Asn450Tyr, Grantham score = 143). Another missense variant at the same amino acid residue (c.1349A>G, p.Asn450Ser) was not classified as likely pathogenic or pathogenic.

BP4

The REVEL score = 0.605, which did not meet the ≤ 0.15 threshold required for BP4.

BP7

This is not a synonymous or non-coding variant.

Approved on: 2022-12-14

Published on: 2022-12-14

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