NM_000104.4(CYP1B1):c.1426T>C (p.Ser476Pro) AND Congenital glaucoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003759042.1

Allele description [Variation Report for NM_000104.4(CYP1B1):c.1426T>C (p.Ser476Pro)]

NM_000104.4(CYP1B1):c.1426T>C (p.Ser476Pro)

Genes:

CYP1B1:cytochrome P450 family 1 subfamily B member 1 [Gene - OMIM - HGNC]
LOC128772254:melanoma risk locus-associated MPRA allelic enhancer 2:38298139 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

2p22.2

Genomic location:

Preferred name:

NM_000104.4(CYP1B1):c.1426T>C (p.Ser476Pro)

HGVS:

NC_000002.12:g.38070928A>G
NG_008386.2:g.10174T>C
NM_000104.4:c.1426T>CMANE SELECT
NP_000095.2:p.Ser476Pro
NC_000002.11:g.38298071A>G

Protein change:

S476P

Links:

dbSNP: rs1682416281

NCBI 1000 Genomes Browser:

rs1682416281

Molecular consequence:

NM_000104.4:c.1426T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital glaucoma
Identifiers:: MONDO: MONDO:0020366; MedGen: C0020302

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004536972	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25978063, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004536972

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 27, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-Phenotype Correlations in CYP1B1-Associated Primary Congenital Glaucoma Patients Representing Two Large Cohorts from India and Brazil.

de Melo MB, Mandal AK, Tavares IM, Ali MH, Kabra M, de Vasconcellos JP, Senthil S, Sallum JM, Kaur I, Betinjane AJ, Moura CR, Paula JS, Costa KA, Sarfarazi M, Paolera MD, Finzi S, Ferraz VE, Costa VP, Belfort R Jr, Chakrabarti S.

PLoS One. 2015;10(5):e0127147. doi: 10.1371/journal.pone.0127147.

PubMed [citation]

PMID:: 25978063
PMCID:: PMC4433271

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004536972.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 476 of the CYP1B1 protein (p.Ser476Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary congenital glaucoma (PMID: 25978063; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 996795). 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 with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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