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]

Variant: NM_000104.4(CYP1B1):c.710C>A (p.Ala237Glu)

CA346328674

1338800 (ClinVar)

Gene: CYP1B1 (HGNC:1545)

Condition: CYP1B1-related glaucoma with or without anterior segment dysgenesis (MONDO:0800472)

Inheritance Mode: Autosomal recessive inheritance

UUID: 66c76f6b-187a-45ef-8513-3682f7e6973e

Approved on: 2025-11-19

Published on: 2025-11-18

HGVS expressions

NM_000104.4:c.710C>A

NM_000104.4(CYP1B1):c.710C>A (p.Ala237Glu)

NC_000002.12:g.38074679G>T

CM000664.2:g.38074679G>T

NC_000002.11:g.38301822G>T

CM000664.1:g.38301822G>T

NC_000002.10:g.38155326G>T

NG_008386.2:g.6423C>A

ENST00000490576.2:c.710C>A

ENST00000610745.5:c.710C>A

ENST00000494864.1:c.-70-3369C>A

ENST00000610745.4:c.710C>A

ENST00000613082.1:n.376-271C>A

ENST00000614273.1:c.710C>A

NM_000104.3:c.710C>A

Likely Pathogenic

PM3_Strong PP3 PM2_Supporting

PS2 PS3 PS1 PP1 BA1 BS4 BS1 PM5 PM4 PM1 BP7 BP4 PVS1

Evidence Links 0

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Criteria Specification: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CYP1B1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Glaucoma VCEP

The c.710C>A variant in CYP1B1 is a missense variant predicted to cause substitution of Alanine by Glutamic acid at amino acid 237 (p.Ala237Glu). The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008475 (1 allele out of 1,179,982), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles. The REVEL score = 0.717, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function. PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699). This variant has been identified in four individuals with a CYP1B1-related phenotype. Two of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 phase unknown and 1 confirmed in trans) and two individuals are homozygous (non-consanguineous) (PMIDs: 21815720, 23218183, 25950505, ClinVar). Total proband points = 2.5, meeting PM3_Strong. In summary, this variant met the criteria to receive a score of 6 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9, adapted from PMID: 32720330) for CYP1B1-related glaucoma with or without anterior segment dysgenesis (ASD) based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1.0, 06.11.2025): PM3_Strong, PP3, PM2_Supporting.

PM3_Strong

This variant has been identified in four individuals with a CYP1B1-related phenotype. Two of these individuals are compound heterozygous for the variant and a pathogenic or likely pathogenic variant (1 phase unknown and 1 confirmed in trans) and two individuals are homozygous (non-consanguineous) (PMIDs: 21815720, 23218183, 25950505, ClinVar). Total proband points = 2.5, meeting PM3_Strong.

PP3

The REVEL score = 0.717, which was within the 0.644-0.772 range for PP3, predicting a damaging effect on CYP1B1 function.

PM2_Supporting

The highest minor allele frequency of this variant was in the European (non-Finnish) genetic ancestry group of gnomAD (v4.1.0) = 0.0000008475 (1 allele out of 1,179,982), which met the ≤ 0.0005 threshold set for PM2_Supporting in a genetic ancestry group of at least 2,000 alleles.

PS2

This variant has not been identified de novo.

PS3

PS3_Supporting was not applied, as although the OddsPath threshold was met (> 2.1), the threshold for abnormal impact on protein function in the assays could not be determined (PMID: 27060699).

PS1

An established likely pathogenic or pathogenic variant causing the same amino acid change has not been identified.

PP1

No segregations have been reported for this variant.

BA1

This criterion was not met as PM2_Supporting has been met.

BS4

Non-segregation involving this variant has not been reported.

BS1

This criterion was not met as PM2_Supporting has been met.

PM5

No other likely pathogenic or pathogenic missense variant at this amino acid residue has been identified.

PM4

This criterion did not apply to this variant.

PM1

This missense variant is located outside well-established functional domains.

BP7

This criterion did not apply to this variant.

BP4

This criterion was not met as PP3 has been met.

PVS1

This criterion did not apply to this variant.

Curation History

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