The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]


Variant: NM_000261.2(MYOC):c.1053C>T (p.Thr351=)

CA1244088

875956 (ClinVar)

Gene: MYOC
Condition: primary open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: 2657505e-a988-4673-a4f5-f61ba93c2fbb

HGVS expressions

NM_000261.2:c.1053C>T
NM_000261.2(MYOC):c.1053C>T (p.Thr351=)
NC_000001.11:g.171636387G>A
CM000663.2:g.171636387G>A
NC_000001.10:g.171605527G>A
CM000663.1:g.171605527G>A
NC_000001.9:g.169872150G>A
NG_008859.1:g.21247C>T
ENST00000037502.11:c.1053C>T
ENST00000637303.1:c.235-2243G>A
ENST00000638471.1:c.*391C>T
ENST00000037502.10:c.1053C>T
ENST00000614688.1:c.*17C>T
NM_000261.1:c.1053C>T

Likely Benign

Met criteria codes 3
BS1 BP7 BP4
Not Met criteria codes 12
BS3 BA1 PS2 PS1 PS3 PS4 PP1 PP3 PM5 PM4 PM6 PM2

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.1053C>T variant in MYOC is a synonymous variant (p.Thr351=). The highest minor allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.001545, which met the ≥ 0.001 threshold set for BS1 (16 alleles out of 10,356, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.197, which met the ≤ 10 threshold for BP4, and the GERP score = -6.34 (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. Although probands with primary open angle glaucoma have been reported 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 -6 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BP4, BP7.
Met criteria codes
BS1
The highest minor allele frequency of this variant was in the Ashkenazi Jewish population of gnomAD (v2.1.1) = 0.001545, which met the ≥ 0.001 threshold set for BS1 (16 alleles out of 10,356, meeting the threshold of ≥ 5 of at least 2,000 observed alleles).
BP7
This synonymous/non-coding variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -6.34 (threshold < 0), indicating a lack of conservation at this site.
BP4
The CADD score (v1.6) = 0.197, 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
BS3
No functional evidence has been found for this variant.
BA1
This criterion was not met as BS1 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.
PS4
Although probands with POAG have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply.
PP1
As BS1 was met, PP1 did not apply and segregations were not counted.
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.
PM2
This criterion was not met as BS1 has been met.
Approved on: 2023-07-05
Published on: 2023-07-05
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