Evidence Repository
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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  • No ClinVar Id was directly found from the curated document

CA1244341

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 021d8f8f-273b-4129-9104-38d47aa4dab9

HGVS expressions

NM_000261.2:c.42G>A
NC_000001.11:g.171652570C>T
CM000663.2:g.171652570C>T
NC_000001.10:g.171621710C>T
CM000663.1:g.171621710C>T
NC_000001.9:g.169888333C>T
NG_008859.1:g.5064G>A
ENST00000037502.11:c.42G>A
ENST00000638471.1:c.42G>A
ENST00000037502.10:c.42G>A
ENST00000614688.1:c.42G>A
NM_000261.1:c.42G>A

Uncertain Significance

Met criteria codes 4
PM2_Supporting BP7 BP4 PS4_Supporting
Not Met criteria codes 11
BA1 BS3 BS1 PS2 PS1 PS3 PP1 PP3 PM5 PM4 PM6

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.42G>A variant in MYOC is a synonymous variant (p.Glu14=). The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002892 (1 allele out of 34,578), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 4.764 which met the ≤ 10 threshold for BP4, and the GERP score = -3.28 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 3 probands with juvenile open angle glaucoma have been reported carrying this variant (PMID: Yadav et al, 2022 pre-print), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 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): BP4, BP7, PS4_Supporting. PM2_Supporting.
Met criteria codes
PM2_Supporting
The highest minor allele frequency of this variant was in the Latino/Admixed American population of gnomAD (v2.1.1) = 0.00002892 (1 allele out of 34,578), which met the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles.
BP7
This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -3.28 (threshold < 0), indicating a lack of conservation at this site.
BP4
The CADD score (v1.6) = 4.764, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.
PS4_Supporting
3 probands with JOAG have been reported carrying this variant (PMID: Yadav et al, 2022 pre-print), which met PS4_Supporting (≥ 2 probands).
Not Met criteria codes
BA1
This criterion was not met as PM2_Supporting has been met.
BS3
No functional evidence has been found for this variant.
BS1
This criterion was not met as PM2_Supporting has been met.
PS2
This variant has not been identified de novo.
PS1
This variant does not involve an amino acid change.
PS3
No functional evidence has been found for this variant.
PP1
No segregations have been reported for this variant.
PP3
This is not a missense variant.
PM5
This is not a missense variant.
PM4
This variant does not cause a protein length change.
PM6
This variant has not been identified de novo.
Approved on: 2023-05-03
Published on: 2023-05-03
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