Submissions for variant NM_000104.4(CYP1B1):c.985G>A (p.Gly329Ser)

gnomAD frequency: 0.00001  dbSNP: rs777678299

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779328	SCV000915914	likely pathogenic	Glaucoma 3A	2018-11-21	criteria provided, single submitter	clinical testing	The CYP1B1 c.985G>A (p.Gly329Ser) missense variant has been reported in one study and found in three individuals with primary congenital glaucoma including one each in a homozygous state, compound heterozygous state with a frameshift variant and heterozygous state (Kim et al. 2011). The variant was absent from 400 control chromosomes and is reported at a frequency of 0.000016 in the Total population of the Genome Aggregation Database. HEK293T cells expressing the p.Gly329Ser variant completely lacked retinol metabolizing activity (Banerjee et al. 2016). Based on the evidence, the p.Gly329Ser variant is classified as likely pathogenic for primary congenital glaucoma. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222636	SCV002500593	likely pathogenic	Primary congenital glaucoma	2022-03-23	criteria provided, single submitter	clinical testing	Variant summary: CYP1B1 c.985G>A (p.Gly329Ser) results in a non-conservative amino acid change located in the conserved helixe I (aa316-349, Jeannot_2007) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249004 control chromosomes (gnomAD and publication data). c.985G>A has been reported in the literature in individuals affected with Primary Congenital Glaucoma, including one homozygote (Kim_2011, Suh_2012). These data indicate that the variant may be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function, where the variant protein was found to be enzymatically null for both estradiol and retinoic acid metabolism (Jeannot_2007, Banerjee_2016). In addition, other missense variants in the same residue (G329D and G329V) have been reported in the Human Gene Mutation Database in association with Primary Congenital Glaucoma (PMID: 17718864, 17893647), supporting the functional importance of this residue of the protein. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as of uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002535652	SCV003290945	pathogenic	Congenital glaucoma	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 329 of the CYP1B1 protein (p.Gly329Ser). This variant is present in population databases (rs777678299, gnomAD 0.01%). This missense change has been observed in individuals with primary congenital glaucoma (PMID: 22942166). ClinVar contains an entry for this variant (Variation ID: 632362). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP1B1 protein function. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 17363580, 27243976). This variant disrupts the p.Gly329 amino acid residue in CYP1B1. Other variant(s) that disrupt this residue have been observed in individuals with CYP1B1-related conditions (PMID: 31024815), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003467305	SCV004215453	likely pathogenic	Anterior segment dysgenesis 6	2024-02-19	criteria provided, single submitter	clinical testing