rs201824781

Positions:

• chr2-38075234-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000104.4(CYP1B1):​c.155C>T​(p.Pro52Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000286 in 1,589,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: CYP1B1 NM_000104.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:5
• Conservation: PhyloP100: 5.53

Genes affected

CYP1B1 (HGNC:2597): (cytochrome P450 family 1 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The enzyme encoded by this gene localizes to the endoplasmic reticulum and metabolizes procarcinogens such as polycyclic aromatic hydrocarbons and 17beta-estradiol. Mutations in this gene have been associated with primary congenital glaucoma; therefore it is thought that the enzyme also metabolizes a signaling molecule involved in eye development, possibly a steroid. [provided by RefSeq, Jul 2008]

CYP1B1-AS1 (HGNC:28543): (CYP1B1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP1B1	NM_000104.4	c.155C>T	p.Pro52Leu	missense_variant	2/3	ENST00000610745.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP1B1	ENST00000610745.5	c.155C>T	p.Pro52Leu	missense_variant	2/3	1	NM_000104.4	P1

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000319 AC: 67 AN: 210080 Hom.: 0 AF XY: 0.000313 AC XY: 36 AN XY: 114932

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.0000966

Gnomad ASJ exome AF: 0.000864

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000484

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.000562

GnomAD4 exome AF: 0.000286 AC: 411 AN: 1436896 Hom.: 1 Cov.: 35 AF XY: 0.000287 AC XY: 205 AN XY: 713554

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000262

Gnomad4 ASJ exome AF: 0.000739

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000446

Gnomad4 NFE exome AF: 0.000296

Gnomad4 OTH exome AF: 0.000503

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152232 Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14 AN XY: 74374

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000461 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.000276 AC: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2020	Reported in two individuals of Italian ancestry with congenital glaucoma who were compound heterozygous for the P52L variant and another missense variant (Giuffre et al., 2011); Reported as a single heterozygous variant in two unrelated individuals, one with open angle glaucoma presenting at age 6, and the other with primary congenital glaucoma; however, this variant has also been observed in an older adult without visual defects, and in siblings and a parent of the patient with primary congenital glaucoma, leading some authors to suggest that this variant may demonstrate incomplete penetrance or that it may be rare variant unrelated to the phenotype (Lopez-Garrido, et al., 2006, Campos-Mollo et al., 2009; Pasutto et al., 2010); Published functional studies have demonstrated that P52L results in reduction but not absence of enzymatic activity as compared to wild-type, suggesting it may be a hypomorphic allele (Jeannot et al., 2007; Pasutto et al., 2010; Campos-Mollo et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31980526, 17363580, 27243976, 21815720, 16862072, 19234632, 30484747, 19643970) -

Glaucoma, primary open angle, juvenile-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2010

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 07, 2023

Variant summary: CYP1B1 c.155C>T (p.Pro52Leu) 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 0.00032 in 210080 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CYP1B1 causing Primary Congenital Glaucoma (0.00032 vs 0.0043), allowing no conclusion about variant significance. c.155C>T has been reported in the literature in several individuals affected with Primary Congenital Glaucoma and primary open angle glaucoma (e.g., Campos-Mollo_2009, Pasutto_2010, Giuffre_2011, Svidnicki_2018). However, the variant has also been reported in unaffected individuals, including a homozygous individual with epileptic encephalopathy but no evidence of anterior chamber ocular abnormality or glaucoma (e.g., Palmer_2016, Lopez-Garrido_2006). These reports suggest the variant represents a hypomorphic allele that may display incomplete penetrance, and therefore these reports do not provide unequivocal conclusions about association of the variant with Primary Congenital Glaucoma. Multiple publications also report experimental evidence evaluating an impact on protein function, finding that the variant protein displays drastically reduced enzymatic activity (ranging from ~0% to 40% of wild-type activity) as well as reduced protein stability (e.g., Jeannot_2007, Campos-Mollo_2009, Pasutto_2010, Lopez-Garrido_2010). The following publications have been ascertained in the context of this evaluation (PMID: 19234632, 21815720, 17363580, 19793111, 16862072, 27270415, 19643970, 30484747). Four ClinVar submitters (evaluation after 2014) have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Irido-corneo-trabecular dysgenesis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Glaucoma 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
Sift4G	Pathogenic	0.0	D;D;.
Vest4		0.75
MVP		0.65
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.44
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201824781; hg19: chr2-38302377;