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Variant: NM_000261.2:c.654G>A

CA421783387

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 4567d3b1-e274-4b15-8fcb-6b17274b9dac

HGVS expressions

NM_000261.2:c.654G>A
NC_000001.11:g.171638673C>T
CM000663.2:g.171638673C>T
NC_000001.10:g.171607813C>T
CM000663.1:g.171607813C>T
NC_000001.9:g.169874436C>T
NG_008859.1:g.18961G>A
ENST00000037502.11:c.654G>A
ENST00000637303.1:c.278C>T
ENST00000638471.1:c.184G>A
ENST00000037502.10:c.654G>A
ENST00000614688.1:c.654G>A
NM_000261.1:c.654G>A

Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 14
PS2 PS1 PS3 PS4 PP1 PP3 PM5 PM4 BA1 PM6 PM2 BS3 BS1 BP7

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.654G>A variant in MYOC is a synonymous variant (p.Glu218=). Although this variant was not found in gnomAD (v2.1.1), the population from which the variant had been reported (South African) was not well represented in this dataset and the variant has been reported in controls (PMID: 21552496). Thus PM2_Supporting was not applied to this variant. The CADD score (v1.6) = 8.018, 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. However, BP7 was not met as this variant had a GERP score = 0.511 (threshold <0), indicating conservation at this site. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Although probands with primary open angle glaucoma have been reported carrying this variant (PMID: 21552496), 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 primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BP4
Met criteria codes
BP4
The CADD score (v1.6) = 8.018, 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.
Not Met criteria codes
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.
PS4
Although probands with POAG have been reported carrying this variant (PMID: 21552496), PM2_Supporting was not met, therefore PS4 did not apply.
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.
BA1
This criterion was not met as PM2_Supporting has been met.
PM6
This variant has not been identified de novo.
PM2
Although this variant was not found in gnomAD (v2.1.1), the population from which the variant had been reported (South African) was not well represented in this dataset and the variant has been reported in controls (PMID: 21552496). Thus PM2_Supporting was not applied to this variant.
BS3
No functional evidence has been found for this variant.
BS1
See comment for PM2_Supporting.
BP7
Although this synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), it had a GERP score = 0.511 (threshold <0), indicating conservation at this site.
Approved on: 2023-02-15
Published on: 2023-02-15
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