2-38074400-GC-AA

Position:

• chr2-38074400-GC-AA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM2 PM5 PP5_Very_Strong

The ENST00000610745.5(CYP1B1):​c.988_989delinsTT​(p.Ala330Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A330S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP1B1 ENST00000610745.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.46

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 Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript ENST00000610745.5 (CYP1B1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-38074401-C-A is described in Lovd as [Pathogenic].
• PP5: Variant 2-38074400-GC-AA is Pathogenic according to our data. Variant chr2-38074400-GC-AA is described in ClinVar as [Pathogenic]. Clinvar id is 2203049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP1B1	NM_000104.4	c.988_989delinsTT	p.Ala330Phe	missense_variant	2/3	ENST00000610745.5	NP_000095.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP1B1	ENST00000610745.5	c.988_989delinsTT	p.Ala330Phe	missense_variant	2/3	1	NM_000104.4	ENSP00000478561	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anterior segment dysgenesis 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 03, 2024

- -

Primary congenital glaucoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 02, 2023

Variant summary: CYP1B1 c.988_989delinsTT (p.Ala330Phe) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249078 control chromosomes (gnomAD). c.988_989delinsTT has been reported in the literature in individuals affected with Primary Congenital Glaucoma (Song_2019, Kim_2011, Macshima_2001). At least one publication reports experimental evidence indicating a severe decrease in metabolic activity (Choudhary_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18622259, 21850185, 31236345, 11527932). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital glaucoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces alanine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 330 of the CYP1B1 protein (p.Ala330Phe). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with primary congenital glaucoma (PMID: 11527932, 21850185, 22942166, 31236345). ClinVar contains an entry for this variant (Variation ID: 2203049). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CYP1B1 function (PMID: 18622259). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-38301543;