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Skeletal dysplasia

Gene: POLR1B

Amber List (moderate evidence)

POLR1B (RNA polymerase I subunit B)
EnsemblGeneIds (GRCh38): ENSG00000125630
EnsemblGeneIds (GRCh37): ENSG00000125630
OMIM: 602000, Gene2Phenotype
POLR1B is in 2 panels

3 reviews

Michael Oldridge (NHS)

Green List (high evidence)

5 unrelated families, all with missense variants, de novo in 3 cases, inherited in affected parent in one, and inherited from mosaic parent (mildly affected?) in another.
3 families have p.Arg1003Cys, 1 p.Arg1003Ser.
4 variants at this specific residue and no reported nonsense/fs/splice site mutations implies dominant negative/gain of function rather than haploinsufficiency as suggested in paper?
Created: 30 Jan 2021, 5:17 p.m. | Last Modified: 30 Jan 2021, 5:17 p.m.
Panel Version: 2.80

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
TCS

Publications

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Promoting this gene from grey to amber, with a recommendation for a green rating following GMS review. 5 families reported plus supportive zebrafish model.
Created: 20 Jan 2021, 1:33 p.m. | Last Modified: 20 Jan 2021, 1:33 p.m.
Panel Version: 2.54
Associated with Treacher-Collins syndrome 4 #618939 (AD) in OMIM

PMID: 31649276 - Sanchez et al 2020 - using exome sequencing they identified 6 patients (5 unrelated families) with heterozygous missense variants in POLR1B. In 3 cases the variants were de novo. One was inherited from the mother, and one from the father who was mosaic for the variant. The c.3007C>T p.Arg1003Cys variant was found in 3 families, and another variant affecting the same residue (c.3007C>A , p.Arg1003Ser) in one other. The 5th family had a different variant (c.2046T>A, p.Ser682Arg). The clinical phenotype was variable with downward slanting palpebral fissures (6/6), Malar hypoplasia (6/6), Conductive deafness (6/6), Cleft palate (3/6), Choanal stenosis/atresia (2/6), Microcephaly(1/6). Using a zebrafish model the looked at polr1b expression profile during zebrafish embryogenesis and morphilino knockdown of polr1b showed abnormal craniofacial development of zebrafish embryos
Created: 20 Jan 2021, 1:31 p.m. | Last Modified: 20 Jan 2021, 1:31 p.m.
Panel Version: 2.53

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Treacher-Collins syndrome 4 OMIM:618939; treacher collins syndrome 4 MONDO:0030067

Publications

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Five unrelated families and a zebrafish model, variant inherited in two of the families, once from affected parent and once from mosaic parent. Note four of the families had missense variants affecting same residue, p.Arg1003
Sources: Literature
Created: 1 May 2020, 9:55 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Treacher-Collins syndrome type 4

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Treacher-Collins syndrome 4 OMIM:618939
  • treacher collins syndrome 4 MONDO:0030067
Tags
for-review
OMIM
602000
Clinvar variants
Variants in POLR1B
Penetrance
None
Publications
Panels with this gene

History Filter Activity

20 Jan 2021, Gel status: 2

Added Tag

Eleanor Williams (Genomics England Curator)

Tag for-review tag was added to gene: POLR1B.

20 Jan 2021, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: POLR1B were changed from Treacher-Collins syndrome type 4 to Treacher-Collins syndrome 4 OMIM:618939; treacher collins syndrome 4 MONDO:0030067

20 Jan 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: polr1b has been classified as Amber List (Moderate Evidence).

1 May 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Zornitza Stark (Australian Genomics)

gene: POLR1B was added gene: POLR1B was added to Skeletal dysplasia. Sources: Literature Mode of inheritance for gene: POLR1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: POLR1B were set to 31649276 Phenotypes for gene: POLR1B were set to Treacher-Collins syndrome type 4 Review for gene: POLR1B was set to GREEN gene: POLR1B was marked as current diagnostic