rs148542782
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000610745.5(CYP1B1):c.1168C>T(p.Arg390Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,613,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R390H) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000610745.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYP1B1 | NM_000104.4 | c.1168C>T | p.Arg390Cys | missense_variant | 3/3 | ENST00000610745.5 | NP_000095.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CYP1B1 | ENST00000610745.5 | c.1168C>T | p.Arg390Cys | missense_variant | 3/3 | 1 | NM_000104.4 | ENSP00000478561 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249632Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135272
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461472Hom.: 0 Cov.: 35 AF XY: 0.0000358 AC XY: 26AN XY: 727048
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Anterior segment dysgenesis 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Glaucoma 3A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The CYP1B1 c.1168C>T (p.Arg390Cys) variant is reported in a total of 12 individuals with primary congenital glaucoma (PCG), including eight homozygotes, three compound heterozygotes, and one heterozygote (Curry et al. 2004; Panicker et al. 2004; Sivadorai et al. 2008; Azmanov et al. 2010). A review by Li et al. (2011) noted the variant in 23 of 542 individuals with PCG, though zygosity is not described. The p.Arg390Cys variant was identified in the above studies in a heterozygous state in one of 715 control individuals and it is reported at a frequency of 0.00003 in the Total population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg390Cys variant is classified as pathogenic for primary congenital glaucoma. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Primary congenital glaucoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2022 | Variant summary: CYP1B1 c.1168C>T (p.Arg390Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249632 control chromosomes. c.1168C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Primary Congenital Glaucoma (example, Reddy_2003, Lim_2013, Jackson_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function was ascertained. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 22, 2021 | - - |
Congenital glaucoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 20, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 390 of the CYP1B1 protein (p.Arg390Cys). This variant is present in population databases (rs148542782, gnomAD 0.006%). This missense change has been observed in individual(s) with primary congenital glaucoma (PMID: 15037581, 15255109). ClinVar contains an entry for this variant (Variation ID: 335952). 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 expected to disrupt CYP1B1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg390 amino acid residue in CYP1B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19536304, 27508083, 30108387). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at