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  • See Evidence submitted by expert panel for details.

Variant: NM_000261.2(MYOC):c.1440C>A (p.Asn480Lys)

CA119175

7951 (ClinVar)

Gene: MYOC
Condition: juvenile open angle glaucoma
Inheritance Mode: Autosomal dominant inheritance
UUID: d0adf58d-a397-461c-b1cd-9d3a527bd978
Approved on: 2022-05-10
Published on: 2022-05-25

HGVS expressions

NM_000261.2:c.1440C>A
NM_000261.2(MYOC):c.1440C>A (p.Asn480Lys)
NC_000001.11:g.171636000G>T
CM000663.2:g.171636000G>T
NC_000001.10:g.171605140G>T
CM000663.1:g.171605140G>T
NC_000001.9:g.169871763G>T
NG_008859.1:g.21634C>A
ENST00000037502.11:c.1440C>A
ENST00000637303.1:c.235-2630G>T
ENST00000638471.1:c.*778C>A
ENST00000037502.10:c.1440C>A
ENST00000614688.1:c.*404C>A
NM_000261.1:c.1440C>A
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Pathogenic

Met criteria codes 5
PM2_Supporting PP3 PP1_Strong PS4_Moderate PS3_Moderate
Not Met criteria codes 10
BS3 BS1 BP4 BP7 PM6 PM5 PM4 PS2 PS1 BA1

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Glaucoma VCEP
The c.1440C>A variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). 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 = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), which met PS4_Moderate (≥ 6 probands). In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting.
Met criteria codes
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.
PP3
The REVEL score = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function.
PP1_Strong
Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family).
PS4_Moderate
13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), which met PS4_Moderate (≥ 6 probands).
PS3_Moderate
Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.

Not Met criteria codes
BS3
This criterion was not met as PS3_Moderate has been met.
BS1
This criterion was not met as PM2_Supporting has been met.
BP4
This criterion was not met as PP3 has been met.
BP7
This is not a synonymous or non-coding variant.
PM6
This variant has not been identified de novo.
PM5
No other missense variants at this amino acid residue have been identified.
PM4
This variant does not cause a protein length change.
PS2
This variant has not been identified de novo.
PS1
The same amino acid change (p.Asn480Lys), resulting from a different nucleotide change (c.1440C>G) (PMID: 18303389), was not classified as pathogenic or likely pathogenic by the ClinGen Glaucoma VCEP without the use of PS1. This variant (c.1440C>A, p.Asn480Lys, ClinVarID: 7951) is used to apply PS1 to the other nucleotide change variant located at this amino acid position (c.1440C>G, p.Asn480Lys, PMID: 18303389).
BA1
This criterion was not met as PM2_Supporting has been met.
Curation History
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